Phenylalkan(en)oic acid

ABSTRACT

The phenylalkan(en)oic acids of the formula: ##STR1## wherein the substituents are defined in the specification.

This is a Divisional of application Ser. No. 08/090,456 filed Jul. 13,1993, now U.S. Pat No. 5,457,122 which is a Divisional of priorapplication Ser. No. 07/921,342 filed Jul. 29, 1992, (now U.S. Pat. No.5,256,686), which is a Divisional of application Ser. No. 07/760,043filed Sep. 13, 1991 (now U.S. Pat. No. 5,155,104), which is a Divisionalof application Ser. No. 07/524,521 filed May 17, 1990 (now U.S. Pat. No.5,086,065).

SUMMARY

This invention is related to phenylalkan(en)oic acids which are usefulfor medicines.

More particularly, this invention is related to:

1) phenylalkan(en)oic acids of the formula: ##STR2## (wherein all of thesymbols are the same meanings as hereinafter defined) and non-toxicsalts thereof,

2) processes for the preparation of them and

3) antagonistic agents on leukotriene (abbreviated as LT hereinafter) B₄containing them as active ingredient.

BACKGROUND

The metabolic routes, in which various compounds are biosynthesized fromthe same mother compound, i.e. arachidonic acid, are called"Arachidonate cascade" as a whole.

Arachidonic acid is metabolized by the action of lipoxygenase, e.g.5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase, to5-hydroperoxyeicosatetraenoic acid (abbreviated as HPETE hereinafter),12-HPETE and 15-HPETE, respectively.

These HPETEs are converted into 5-hydroxyeicosatetraenoic acid(abbreviated as HETE hereinafter), 12-HETE and 15-HETE, respectively, bythe action of peroxidase which convert a hydroperoxy group to a hydroxygroup. Furthermore, LTA₄ is also produced from 5-HPETE. LTA₄ isconverted into LTB₄ and LTC₄. LTC₄ is converted into LTD₄ by the actionof γ-glutamyl transpeptidase. Moreover, it has been defined that LTD₄ ismetabolized to LTE₄ (see Biochem. Biophys. Res. Commun., 91, 1266 (1979)and Prostaglandins, 19 (5), 645 (1980)).

Moreover, the action of LTB₄ has been gradually identified recently.Namely, it as been identified that LTB₄ having the following structure:##STR3## (wherein the double bonds between 6th- and 7th- carbon, 8th-and 9th-carbon, 10th- and 11th- carbon and 14th- and 15th-carbon, are Z,E, E and Z, respectively), possesses a powerful action ofpolymorphonuclear leukocytes (PMNLs) accumulation and PMNLs adhesion,and PMNLs degranulation (see Nature, 286,264 (1980), Proc. Nat. Acad.Sci. USA, 78, 3887 (1981) and J.Biol. Chem., 256, 5317 (1981)). Moreoverit has been considered that LTB₄ promotes the release of arachidonicmetabilites by attacking various cells as it has the powerful actionlike calcium ionophore (see J. Biol. Chem., 257, 4746 (1982)).

Moreover, LTB₄ in high concentration has been detected at the sites ofvarious inflammation, for example, rheumatism, spinal arthritis (seeKlickstein L. B., Shapleigh, C. and Goetzl, E. J. (1980) J.Clin.Invest., 66, 1166-1170), gout (Rae, S. A., Davidson, E. M. and Smith, M.J. H. (1982) Lancet II 1122-1123), psoriasis (see Grabbe, J.,Czarnetzki, B. M., Rosenbach, T. and Mardin, M. (1984) J. Invest.Dermatol., 82, 477-479), ulceractive colitis (see Sharon, P. andStenson, W. F. (1984) Gastroenterology 86, 453-460), respiratory disease(see O'Driscoll, B. R., Cromwell, O. and Kay, A. B. (1984) Clin. Exp.,Immunol., 55, 397-404). The fact described above shows that LTB₄ isdeeply related to various inflammation.

Accordingly, the antagonistic agents on LTB₄ are considered to be usefulas anti-inflammatory agents and antiallergic agents.

RELATED ARTS

In recent research, some compounds having an antagonism on LTB₄ havebeen reported.

For example,

1) in the literatures (Feinmark, J., Lindgren, J. A., Claesson, H. E.,Malmsten, C., and Samuelsson, B. (1981) FEBS Lett., 136, 141-144;Showell, H. J., Oherness. I. G., Marfat, A., and Corey, E. J. (1982)Biochem. Biophy. Res. Commun., 106, 741-747), the compound of theformula: ##STR4## has been disclosed, 2) in the specification ofJapanese Patent Kokai No. 59-33258, i.e. Derwent accession No.84-173740/28, the compounds of the formula: ##STR5## wherein R^(1b) ishydrogen or C1-4 alkyl; R^(2b) is C1-8 alkylene; and R^(3b) is hydrogen,

C1-15 alkyl or the group of the formula --CH₂ --A_(b) --R^(4b) (whereinA_(b) is cis-vinylene or ethynylene; and

R^(4b) is C1-12 alkyl); have been disclosed,

3) in the specification of Japanese Patent Kokai No. 59-95249, i.e.Derwent accession No. 84-84453/14, the compounds of the formula:##STR6## wherein Yc is nitrogen or aminomethyl; R^(1C) is hydrogen orC1-4 alkyl; R^(2c) is C1-8 alkylene; and R^(3c) is C1-15 alkyl or thegroup of the formula: --CH₂ --Ac--R^(4c)

(wherein Ac is cis-vinylene or ethynylene; and R^(4c) is C1-12 alkyl);have been disclosed and more recently

4) in the specification of Japanese Patent Kokai No. 63-188644, i.e.European Patent Publication No. 276065, the compounds of the formula:##STR7## (wherein R^(1d) hydrogen or --COOR^(d), Zd is--(CH₂)nd--orphenylene (nd is 1-8); R^(2d) is hydroxy, halogen or --O--(CH₂)md--Yd;R^(3d) is C1-6 alkyl, C1-6 alkanoyl, C2-4 alkenyl, C1-4 alkoxy, C1-3alkyl substituted by hydroxy or --CH₂ --Dd; Ad is bond or straight-chainor branched-chain C1-10 alkylidene; R^(4d) is C1-6 alkyl, C2-6 alkenylor C2-6 alkynyl, hydroxy, --CN, halogen, --N₃, --NR^(5d) R^(6d),--COR^(7d),--S(O)pd--(C1-4 alkyl), 1,2,4-triazol-1-yl, 5-tetrazolylwhich may be substituted by C1-4 alkyl or --(CH₂)gdCOOR^(d'), phenylwhich may be substituted by 1 or 2 of halogen, --CN, C1-3 alkyl, --CF₃,--CH₂ CN, --CH₂ Br, C1-4 alkoxy, --S(O)pd--(C1-4 alkyl), acetenyl,acetyl, COOR^(d'), 5-tetrazolyl, or 5-tetrazolyl substituted by C1-4alkyl or--(CH2)gd--COOR^(d') (each R^(d') is hydrogen or C1-4 alkyl; mdis 1-4; gd is 1-4; Yd is hydrogen or --CN; Dd is halogen. C1-4 alkoxy or--S--(C1-4 alkyl)); R^(5d) and R^(6d) are independently hydrogen, C1-3alkyl or C2-4 alkanoyl, or R^(5d) and R^(6d), taken together with anitrogen atom to which they are attached, form morpholino; R^(7d) ishydroxy, C1-4 alkoxy, halogen, --NR^(5d) R^(6d), --NHOH,5-tetrazolylamino or C 1-3 alkyl; each pd is 0-2; with the proviso thatwhen Ad is bond, R^(4d) should be C1-6 alkyl or optionally substitutedphenyl, and when one of R^(5d) and R^(6d) is C2-4 alkanoyl then theother should be hydrogen; and the pharmaceutically acceptable salts havebeen disclosed,

5) in the specification of Japanese Patent Kokai No. 63-188646, i.e.European Patent Publication No. 276064, the compounds of the formula;##STR8## (wherein Ae and De are independently --CN, --COOR^(1e) or5-tetrazolyl; ne is 0 or 1;

Ye is --O--, --CO--, --CH₂ CO--, --C(═NOH)--, --CHOH--, --CH₂ -- or--C(═CH₂);

me is 0-3;

Ee is --O-- or --CH₂ --;

pe is 0-16;

Ze is hydrogen or --Ge--Qe;

Ge is bond, --O--, --S(O)te--, --NH-- or --CH═CH--,

Qe is phenyl or phenyl substituted by 1 or 2 of halogen, C1-3 alkyl,C1-3 alkoxy, nitro, amino, trifluoromethyl, hydroxy and --S(O)pe --(C1-3alkyl); pe and te are each 0-2; R^(1e) is hydrogen or C1-3 alkyl); andthe pharmaceutically acceptable salts have been disclosed.

DISCLOSURE OF THE INVENTION

The present invention is related to

1) phenylalkan(en)oic acid of the formula: ##STR9## wherein A is i)--NHCO--

ii) --O--

iii) --NHSO₂ --

iv) --CO--

v) --CH₂ -- or

vi) --CH(OH)--;

W is i) C1-13 alkylene,

ii) phenylene or ##STR10## R¹ is i) hydrogen, ii) C1-4 alkyl,

iii) --COOH,

iv) saturated or unsaturated, 4-7 membered mono-cyclic hetero ringcontaining one nitrogen as a hetero atom or saturated or unsaturated,4-7 membered monocyclic hetero ring containing one nitrogen as a heteroatom substituted by an oxo group, ##STR11## vi) --CH₂ OH or A, takentogether with W and R¹, is ##STR12## two R² are, same or different, i)hydrogen,

ii) C1-4 alkyl or

iii) 4-7 membered, saturated or unsaturated, mono-cyclic hetero ringcontaining two or three of nitrogen and sulfur in total, or two R²,taken together with a nitrogen to which they are attached, formsaturated or unsaturated,

i) 7-14 membered, bi-or tri-cyclic hetero ring containing one nitrogenas a hetero atom, or

ii) 4-7 membered, mono-cyclic hetero ring containing two or three ofnitrogen and oxygen in total;

Y is ethylene or vinylene;

D is i) --Z--B or ##STR13## Z is C3-11 alkylene or alkenylene B is##STR14## Z, taken together with B, is C3-22 alkyl; R³ is i) hydrogen,

ii) halogen,

iii) C1-8 alkyl, alkoxy or alkylthio, or

iv) C2-8 alkenyl, alkenyloxy or alkenylthio;

n is 1-3;

R⁴ is C1-7 alkylene;

R⁵ is i) C1-12 alkyl,

ii) C2-12 alkenyl,

iii) C5-7 cycloalkyl or

iv) phenethyl or phenethyl wherein the ring is substituted by one C1-4alkoxy;

Two R⁶ are, same or different,

i) C1-7 alkyl,

ii) benzyl or

iii) phenyl or phenyl wherein the ring is substituted by one C1-4 alkyl;and

Two R⁷ are, same or different, C1-4 alkyl;

with the proviso that

i) --A--W--R¹ should bind to 3- or 4- carbon in benzene ring, and

ii) when W is phenylene or ##STR15## A should not represent --O--,--CO--, --CH₂ -- or --CH(OH)--; and non-toxic salts thereof,

2) processes for the preparation of them and

3) antagonistic agent on leukotriene B₄ containing them as activeingredient.

The present invention includes all isomers unless otherwise specified.For example, alkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenylthio,alkylene and alkenylene groups mean straight-chain or branched-chainalkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenylthio, alkylene andalkenylene groups, respectively, and the double-bond in alkenylene,alkenyl, alkenyloxy and alkenylthio groups include E, Z and the mixtureof E and Z. In case of existing branched-chain alkyl group etc., thepresent invention includes the isomers caused by existing asymmetricalcarbon atoms.

In the formula (I), C1-13 alkylene group shown by W are methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene, nonamethylene, decamethylene,undecamethylene, dodecamethyiene, tridecamethylene group and isomersthereof.

In the formula (I), C1-4 alkyl group shown by R¹, R², substituent in R⁶,and R⁷ are methyl, ethyl, propyl, butyl group and isomers thereof.

In the formula (I), 4-7 membered, saturated or unsaturated, mono-cyclichetero ring containing one nitrogen as a hetero atom, shown by R¹ are,for example, pyrrole, pyridine ring and partially or fully saturatedrings thereof, such as pyrrolidine. These rings may be substituted byone oxo group. 4-7 membered, saturated or unsaturated, mono-cyclichetero ring containing two or three of nitrogen and sulfur in total,shown by R² are, for example, thiazole, isothiazole, thiadiazoline ringand partially or fully saturated rings thereof.

In the formula (I), saturated or unsaturated, 7-14 membered, bi- ortri-cyclic hetero ring containing one nitrogen as a hetero atom, shownby two R², taken together with a nitrogen to which they are attachedare, for example, indole, isoindole, quinoline, isoquinoline, carbazole,acridine ring and partially or fully saturated rings thereof. Saturatedor unsaturated, 4-7 membered, mono-cyclic hetero ring containing two orthree of nitrogen and oxygen in total, shown by two R², taken togetherwith a nitrogen are, for example, oxazole, isooxazole, furazan ring andpartially or fully saturated rings thereof and morpholine ring.

In the formula (I), C3-11 alkylene and alkenylene groups shown by Z aretrimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene, nonamethylene, decamethylene,undecamethylene group and isomers thereof and the groups containing 1 to3 of double bonds therein.

In the formula (I), C1-8 alkyl group shown by R³ are methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.C1-8 alkoxy group shown by R³ are methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof. C1-8alkylthio group shown by R³ are methylthio, ethylthio, propylthio,butylthio, pentylthio, hexylthio, heptylthio, octylthio group andisomers thereof.

In the formula (I), C2-8 alkenyl group shown by R³ are the groupscontaining 1 to 3 of double bonds in ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl group and isomers thereof. C2-C8 alkenyloxy groupshown by R³ are the groups containing 1 to 3 of double bonds in ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group andisomers thereof. C2-C8 alkenylthio group shown by R³ are the groups 1 to3 of double bonds in ethylthio, propylthio, butylthio, pentylthio,hexylthio, heptylthio, octylthio group and isomers thereof. Halogenshown by R³ are, fluorine, chlorine, bromine and iodine atom.

In the formula (I), C3-22 alkyl group shown by Z, taken together with Bare propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl, nonadecyl, icosyl, henicosyl, docosyl group and isomersthereof.

In the formula (I), C1-7 alkylene group shown by R⁴ are methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene group and isomers thereof.

In the formula (I), C1-12 alkyl group shown by R⁵ are methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl group and isomers thereof. C2-12 alkenyl group shown by R₅ arethe groups containing 1 to 3 of double bonds in ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl group andisomers thereof. C5-7 cycloalkyl group shown by R⁵ are cyclopentane,cyclohexane, cycloheptane. C1-4 alkoxy group shown by substituents in R⁵are methoxy, ethoxy, propoxy, butoxy group and isomers thereof.

In the formula (I), C1-7 alkyl group shown by R⁶ are methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl group and isomers thereof.

Comparison with related arts

The compounds of the formula (I), of the present invention are quitenovel.

More concretely, the compounds wherein W represents an alkylene, of thepresent invention are quite novel in structure. Furthermore, it can notbe expected from the information of the related arts that the compoundshaving these structures, possess an antagonism on leukotriene B₄.

The compounds wherein W represents a phenylene or the group of theformula: ##STR16## of the present invention are also quite novel. Thecompounds of the formula (d) have the structure in which the groupcorresponding to A in the formula (I) is carbonyl group, and those ofthe formula (e) have the structure in which the group corresponding to Ain the formula (I) is oxy, carbonyl, methylene or hydroxymethylenegroup. On the other hand, the compounds wherein W represents a phenyleneor the group of the formula: ##STR17## of the present invention, havethe group of the formula: --NHCO-- or --NHSO₂ -- as the group A.Therefore, the compounds of the present invention are quite differentfrom the related arts in structure in that the groups shown by Arepresent quite different groups.

Furthermore, it can not be expected that an antagonism on leukotriene B₄was held in the compounds wherein oxy, carbonyl, methylene orhydroxymethylene group is replaced by the groups of the formula --NHCO--or --NHSO₂ --.

Salts

The compounds of the formula (I) may be converted into the correspondingsalts by the known method. Non-toxic and water-soluble salts arepreferable. Suitable salts, for example, are followings:

salts of alkaline metal (sodium, potassium etc.), salts of alkalineearth metal (calcium, magnesium etc.), ammonium salts, salts ofpharmaceutically acceptable organic amine (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,N-methyl-D-glucamine etc.).

Process for the Preparation of the Compounds of the Present Invention

The compounds of the formula (I), of the present invention may beprepared by

1) saponificating the compound of the formula: ##STR18## wherein A¹ isi) --NHCO-- or

ii) --NHSO₂ --;

R¹¹ is

i) the group of R^(1a)

(wherein R^(1a) is hydrogen, saturated or unsaturated, 4-7 memberedmono-cyclic hetero ring containing one nitrogen as a hetero atom,unsubstituted or substituted by an oxo group or C1-C4 alkyl),

ii) --CO₂ H or

iii) the group shown by: ##STR19## or A¹, taken together with W and R¹¹,is ##STR20## t-Bu is tert-Butyl group; and the other symbols are thesame meanings as described hereinbefore;

or the compounds of the formula: ##STR21## wherein R¹⁶ is i) --CO₂ H or

ii) the group of the formula: ##STR22## and the other symbols are thesame meanings as described hereinbefore;

with using an acid (formic acid, trifluoroacetic acid etc.) in an inertorganic solvent (methanol, tetrahydrofuran etc.),

2) saponificating the compound of the formula: ##STR23## wherein, all ofthe symbols are same meaning as described hereinbefore; the compound ofthe formula: ##STR24## wherein R¹² is i) the group of R^(1a),

ii) the group shown by ##STR25## iii) --CO₂ CH₃ or IV) ##STR26## and theother symbols are the same meanings as described hereinbefore;

the compound of the formula: ##STR27## wherein A¹¹ is --NHSO₂ --; R¹³ is

i) the group of --R^(1a)

ii) the group shown by ##STR28## iii) --CH₂ OCHO or iv) --CO₂ H or

A¹¹, taken together with W and R¹³, is ##STR29## the other symbols arethe same meanings as described hereinbefore; the compound of theformula: ##STR30## wherein Et is ethyl; R¹⁴ is

i) the group of --R^(1a),

ii) the group shown by ##STR31## or iii) --CO₂ Et; and

the other symbols are the same meanings as described hereinbefore;

the compound of the formula: ##STR32## wherein A² is i) --O-- or

ii) --CH₂ --;

R¹⁵ is

i) hydrogen or

ii) acetyl group; and

the other symbols are the same meanings as described hereinbefore;

the compound of the formula: ##STR33## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR34## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR35## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula; ##STR36## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR37## wherein R¹⁷ is i) the group shownby R ##STR38## ii) --CH₂ OH or iii) --CO₂ H; and

the other symbols are the same meanings as described hereinbefore;

the compound of the formula: ##STR39## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR40## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR41## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR42## wherein all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR43## wherein R¹⁸ is i) --CO₂ Et,

ii) the group shown by ##STR44## or iii) --CH₂ OH; and

the other symbols are the same meanings as described hereinbefore;

the compound of the formula: ##STR45## wherein, all of the symbols arethe same meanings as described hereinbefore;

the compound of the formula: ##STR46## wherein R¹⁹ is i) the group shownby ##STR47## or ii) --CO₂ Et; and

the other symbols are the same meanings as described hereinbefore; or

the compound of the formula: ##STR48## wherein all of the symbols arethe same meanings as described hereinbefore;

with using an alkali (sodium hydroxide etc.) in an inert organic solvent(methanol, tetrahydrofuran etc.) or

3) reducing the compound of the formula: ##STR49## wherein all of thesymbols are the same meanings as described hereinbefore;

with using reducing agent (sodium borohydride etc.) in an inert organicsolvent (methanol etc.).

Process for the Preparation of the Intermediates

The compounds of the formulae (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),(XVIII), (XIX), (XX), (XXI) and (XXII) may be prepared by the stepsshown in the following scheme A!, B!, C!, D! and E!. ##STR50## (Inschemes,

R^(1a) is hydrogen,

saturated or unsaturated, 4-7 membered mono-cyclic hetero ringcontaining one nitrogen as a hetero atom, which ring is unsubstituted orsubstituted by an oxo group, or C1-4 alkyl;

Z¹, taken together with B¹, is C3-22 alkyl;

Z² is C3-11 alkylene or alkenylene;

B² is the group shown by ##STR51## p is 2-8; r is 2 or 3;

THP is tetrahydropyran-2-yl;

Ms is mesyl;

Ac is acetyl;

p-TsOH is p-toluenesulfonic acid;

SO₃ Py is the complex of sulfur trioxide and pyridine;

DMSO is dimethyl sulfoxide;

Py is pyridine;

DCC is 1,3-dicyclohexylcarbodiimide; and the other symbols are the samemeanings as described hereinbefore.)

In each reaction in the present specification, products may be purifiedby conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction, or after a seriesof reactions.

Starting Materials

The starting materials and each reagents in the present invention areknown or may be prepared by the known methods.

Effect

An antagonism on leukotriene B₄ of the compounds of the presentinvention has been confirmed by the following experimental results.

i) Binding affinity of ³ H-LTB4 antagonist to human PMNL LTB₄ receptor

Human PMNLS (1×10⁷ cells) were incubated with 1 nM ³ H-LTB₄ in Hanksbalanced salt solution (1 ml) at 4° C. for 20 min. in the presence orabsence of increasing concentrations of unlabeled LTB₄ or variouscompounds. Free ³ H-LTB₄ was separated from PMNLs-bound ligands byvacuum filtration through Whatman GF/B or C glass fiber filters. Thefilters were then washed rapidly 4 times with 2.5 ml of the ice-coldphosphate buffered saline. The radioactivity retained in the filter wasdetermined by liquid scintillation counting. Specific binding wasdefined as the difference between total binding and binding in thepresence of 3 μM LTB₄ (nonspecific binding). The inhibitory effect ofspecific ³ H-LTB₄ binding was calculated from the following equation.

    The percentage of inhibition (%)=100-(B.sub.1 /B.sub.0 ×100)

B₁ : specific ³ H-LTB₄ binding in presence of antagonist

B₀ : specific ³ H-LTB₄ binding in absence of antagonist

The results are shown in the following table 1.

                  TABLE 1                                                         ______________________________________                                        Ex. No. of the                                                                           IC.sub.50 value                                                                          Ex. No. of the                                                                           IC.sub.50 value                              compounds  (μM)    compounds  (μM)                                      ______________________________________                                        1          0.13        6 (c)     0.20                                         1 (a)      0.045       7 (a)     0.030                                        1 (c)      1.0         9         0.010                                        1 (e)      0.080      10         0.013                                        1 (f)      0.050      10 (c)     1.0                                          1 (i)      0.40       11         0.045                                        1 (j)      0.20       12         0.0070                                       1 (m)      0.49       12 (b)     0.0060                                       1 (n)      0.070      13         0.045                                        1 (o)      0.020      14         0.070                                        1 (q)      0.050      16         0.090                                        1 (r)      1.1        18         0.025                                        1 (s)      0.17       19         0.030                                        1 (t)      0.22       20         0.0036                                       1 (u)      0.080      29         0.018                                        2          0.040      30         0.016                                        2 (a)      0.20       30 (a)     0.070                                        2 (b)      0.020      30 (b)     0.15                                         3          0.17       31         0.040                                        3 (a)      0.20       31 (a)     0.015                                        4          0.090      32         0.050                                        4 (b)      0.060      33         0.015                                        5          0.020      34         0.020                                        5 (b)      0.30       35         0.20                                         5 (c)      0.70       36         0.15                                         5 (e)      0.35       37         0.0060                                       6          0.080      38         0.12                                         6 (b)      0.030      39         0.023                                                              40         0.17                                         ______________________________________                                    

ii) Inhibition of Human PMNLs aggregation

The purified human PMNLs were suspended in Hank's-0.5% BSA medium (pH7.4) at 1×10⁷ cells/ml. The PMNLs suspensions (200 μl) were preincubatedwith varying concentrations of tasted compounds for 3 min at 37° C.prior to the addition of 10⁻⁸ M solution (10 ml) of LTB₄ in Hank'ssolution. PMNLs aggregation in vitro was performed with a multichannelplatelet aggregometer. Aggregation was detected as change in lighttransmission with an aggregometer.

The results are shown in the following table 2.

                  TABLE 2                                                         ______________________________________                                        Ex. No. of the                                                                           IC.sub.50 value                                                                          Ex. No. of the                                                                           IC.sub.50 value                              compounds  (μM)    compounds  (μM)                                      ______________________________________                                         1 (a)     3.6        31         6.0                                           1 (o)     3.0        31 (a)     1.9                                           2 (b)     7.4        32         5.4                                          16         7.0        34         0.81                                         20         2.0        37         1.7                                          30         0.84       38         4.9                                          30 (a)     1.1                                                                ______________________________________                                    

The results in the Table 1 and Table 2 show that the compounds of thepresent invention possess an antagonism on leukotrine B₄.

Toxicity

It was confirmed that the toxicity of the compounds, of the presentinvention were very low. For example, the acute toxicity (LD₅₀) of thecompounds in Example 30 and 31 (a) are 3.9 g/kg and 2.2 g/kg,respectivity, in oral administration and 175 mg/kg and 260 mg/kg,respectivity, in intravenous administration in mouse. Accordingly, itwas confirmed that the compounds of the present invention were usefulfor pharmaceutical agent.

Application for Pharmaceuticals

The compounds of the formula (I), of the present invention, are usefulfor prevention and/or treatment for allergic dermatosis, rheumatism,gout, psoriasis, arthritis, trychophytosis, cardiac infarction etc. inmammals including human beings since they possess an antagonism on LTB₄

For the purpose above described, the compounds, of the formula (I), ofthe present invention and non-toxic salts thereof may be normally byadministered systemically or partially usually by oral or parenteraladministration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 1mg and 100 mg, by parenteral administration up to several times per day,or continuous administration between 1 and 24 hrs. per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

When administration of the compounds of the present invention, it isused as solid compositions, liquid compositions or other compositionsfor oral administration, as injections, liniments or suppositories etc.for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules. Capsules containhard capsules and soft capsules.

In such compositions, one or more of the active compound(s) is or are,admixed with at least one inert diluent (lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate etc.) Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (magnesiumstearate etc.), disintegrating agents (cellulose calcium glycolateetc.), stabilizing agent (lactose etc.), and assisting agent fordissolving (glutamic acid, asparaginic acid etc.).

The tablets or pills may, if desired, be coated with film of gastric orenteric material (sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate etc.), or be coated with morethan two films. And further, it may be include capsules of absorbablematerials such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable solutions, emulsions, suspensions, syrupsand elixirs.

In such compositions, one or more of the active compound(s) is or arecomprise in inert diluent(s) commonly used in the art (purified water,ethanol etc.).

Besides inert diluents, such compositions may also comprise adjuvants(wetting agents, suspending agent etc.), sweetening agents, flavouringagents, perfuming agents and preserving agent.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s).

Spray compositions may comprise additional substances other than inertdiluents: e.g. stabilizing agents (sodium sulfite etc.), isotonic buffer(sodium chloride, sodium citrate, citric acid etc.)

For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. In such compositions,one more of active compound(s) is or are admixed at least one of inertaqueous diluent(s) (distilled water for injection, physiological saltsolution etc.) or inert non-aqueous diluent(s) (propylene glycol,polyethylene glycol, olive oil, ethanol, POLYSOLBATE80 (registered trademark) etc.).

Injections may comprise additional other than inert diluents: e.g.preserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agent (lactose etc.), assisting agents such asassisting agents for dissolving (glutamic acid, asparaginic acid etc.).

They may be sterilized for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They also be manufactures in the form ofsterile solid compositions, for example, by freeze-drying, and which canbe dissolved in sterile water or some other sterile diluents forinjection immediately before used.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments (ointment etc.), suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by known methods.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples are illustrated thepresent invention, but not limit the present invention.

The solvents in the parentheses show the eluting or developing solventsand the ratios of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "IR" was measured by the KBr tablet methodand "NMR" was measured in a mixture of chloroform-d and methanol-d₄,respectively.

The compounds of the formula (I) can be named as derivatives of analkan(en)oic acid with the numbering of the benzene ring as follows:##STR52## (when Y is ethylene) The above compound can be called3-(1-substituted-(3 or 4)-substitutedbenzen-2-yl)propionic acid.

Reference Example 1

t-Butyl 3-(2-hydroxy-5-nitrophenyl)-2E-acrylate ##STR53##

Sodium hydride (content:62%, 3.3g) was suspended in tetrahydrofuran (30ml). The suspension was ice-cooled in an atmosphere of argon gas. Asolution of t-butyl diethylphosphonoacetate (20.9 g) in tetrahydrofuran(20 ml) was added to the suspension. The mixture was stirred for 15 min.at room temperature. A solution of 2-hydroxy-5-nitrobenzaldehyde (6.6 g)in tetrahydrofuran (20 ml) was gradually added to the mixture often withice-cooling. The mixture was stirred for 10 min. at room temperature.Acetic acid was gradually added to the mixture until pH of the mixturewas down to 5.0. The reaction mixture was gel-filtered with using YMCgel. Moreover the gel was washed with ethyl acetate. A mixture of thefiltrate and washings was evaporated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to givethe title compound (10.0 g) having the following physical data.

TLC(n-hexane:ethyl acetate=3:2):Rf 0.40.

Reference example 2

t-Butyl 3-(2-hydroxy-5-aminophenyl)propionate ##STR54##

The unsaturated ester (prepared in reference example 1; 8.0 g) wasdissolved in ethanol (100 ml). A suspension of 10% Palladium-Carbon (1.0g) in ethanol (10 ml) was added to the solution. The mixture was stirredfor 2 hr. at room temperature under an atmosphere of hydrogen gas. Thereaction solution was filtered with using Celite 545. Celite was washedwith ethanol. The mixture of the filtrate and washings was evaporated togive the residue (7.1 g), containing the title compound having thefollowing physical data. The residue was used in next reaction withoutpurification.

TLC(n-hexane:ethyl acetate=3:2): Rf 0.22.

Reference Example 3

t-Butyl 3-1-hydroxy-4-(4-methoxycarbonylbutanamido)benzen-2-yl!propionate##STR55##

The ester (prepared in reference example 2; 6.4 g) was dissolved inmethylene chloride (100 ml). Pyridine (5.0 ml) was added to thesolution. 4-methoxycarbonylbutanoyl chloride (3.75 ml) was added to thesolution with ice-cooling. The mixture was stirred for 10 min. at roomtemperature. Ice was added to the reaction mixture. The mixture wasextracted with ethyl acetate. The extract was washed with 2Nhydrochloric acid, saturated aqueous solution of sodium bicarbonate,followed by saturated brine, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=2:3→3:8) to give the title compound (9.6 g)having the following physical data.

TLC(n-hexane:ethyl acetate=2:3): Rf 0.51.

Reference Example 4

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-methoxycarbonylbutanamido)benzen-2-yl!propionate##STR56##

Phenol (580 mg; prepared in reference example 3) and sodium hydride(content: 62%, 62 mg) were dissolved in dried dimethylformamide (2 ml).The solution was stirred at room temperature in an atmosphere of argongas. A solution of 6-(p-methoxyphenyl)-5E-hexenol methanesulfonate (450mg) in dried dimethylformamide (1 ml) was added to the solution. Themixture was stirred for 2 hr. at 60° C. The reaction mixture was pouredinto a mixture of ice and 1N hydrochloric acid (10 ml). The mixture wasextracted with--ethyl ether--ethyl acetate (1:1). The extract was washedwith water, saturated aqueous solution of sodium bicarbonate, followedby brine, dried over anhydrous magnesium sulfate and evaporated. Theresidue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (265 mg) having thefollowing physical data.

TLC(n-hexane:ethyl acetate=1:2):Rf 0.30.

Reference Example 5

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-carboxylbutanamido)benzen-2-yl!propionate.##STR57##

The ester (265 mg; prepared in reference example 4) was dissolved in amixture of methanol (3 ml) and tetrahydrofuran (2 ml). A 1N aqueoussolution of sodium hydroxide (1.0 ml) was added to the solution. Thesolution was stirred for 3 hr at room temperature. The reaction solutionwas diluted with water. 1N hydrochloric acid (1.5 ml) was added to thesolution. The mixture was extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfate and evaporatedto give the residue contained the title compound having the followingphysical data. The residue was used in next reaction withoutpurification.

TLC(ethyl acetate): Rf 0.10.

Reference Example 6

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(5-oxo-5-morpholinopentanamido)benzen-2-yl!propionate##STR58##

The ester (86 mg; prepared in reference example 5) was dissolved in amixture of dried tetrahydrofuran (1 ml) and triethylamine (44 μl). Ethylchloroformate (23 μl) was gradually added to the solution at -10° C. Thesolution was stirred for 15 min. at -10° C. Morpholine (generally 0.5ml) was added to the solution. The mixture was stirred for 30 min. at 0°C. and then for 30 min. at room temperature. The reaction mixture waspoured So a mixture of ice and 2N hydrochloric acid (10 ml). The mixturewas extracted with ethyl acetate. The extract was washed with 2Nhydrochloric acid, water, an aqueous solution of sodium bicarbonate,followed by brine, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (ethyl acetate) to give the title compound (74 mg) having thefollowing physical data.

TLC(ethyl acetate) Rf 0.10;

MS: m/z 608(M⁺), 552, 184, 156, 121.

Reference Example 7

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(5-hydroxypentanamido)benzen-2-yl!propionate##STR59##

The ester (210 mg; prepared in reference example 5) was dissolved intetrahydrofuran (2 ml). Triethylamine (56 μl) was added to the solution.Ethyl chloroformate (35 μl) was added to the solution at -10°. Thesolution was stirred for 10 min. at -10° C. Sodium borohydride (25 mg)and methanol (0.3 ml) was gradually added to a half quantity of thereaction solution. The solution was stirred for 15 min. The reactionsolution was diluted with ethyl acetate. The solution was washed with 1Nhydrochloric acid, saturated aqueous solution of sodium bicarbonate,followed by saturated brine, dried over anhydrous magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=1:2→1:3) to give the title compound (51 mg)having the following physical data.

TLC(n-hexane:ethyl acetate=1:2):Rf 0.32;

MS: m/z 511 (M⁺), 455.

Reference Example 8

1-Hydroxy-2-dimethoxymethyl-4-nitrobenzene ##STR60##

2-Hydroxy-5-nitrobenzaldehyde (3.34 g) was dissolved in methanol (30ml). Trimethyl orthoformate (20 ml) and then Dowex 50 W×8 (H⁺form)(generally 2 ml) were added to this solution. The mixture wasstirred for 30 min. at room temperature. The resin was removed from thereaction mixture by passing the mixture through an alumina. The filtratewas evaporated to give the title compound (4.0 g) having the followingphysical data.

TLC(n-hexane:ethyl acetate=2:1):Rf 0.21;

MS: m/z 213 (M⁺), 195, 181.

Reference Example 9

t-Butyl 3-1-hydroxy-4-(4-methoxycarbonylbutanamido)benzen-2-yl!-2E-acrylate##STR61##

The amide (853 mg), which was obtained with using the acetal (549 mg;prepared in reference example 8) by the same procedure as referenceexample 2→reference example 3, was dissolved in 5% hydrous acetone (10ml). p-Toluenesulfonic acid (100 mg) was added to the solution. Thesolution was stirred for 1 hr. at room temperature. The reactionsolution was diluted with ethyl acetate. The solution was washed withsaturated aqueous solution of sodium bicarbonate, followed by saturatedbrine, dried over anhydrous magnesium sulfate and then evaporated. Theresidue was recrystallized from n-hexane--ethyl acetate (=1:1) to givethe corresponding aldehyde (711 mg).

Sodium hydride (content:62%; 110 mg) was suspended to tetrahydrofuran(10 ml). The suspension was ice-cooled in an atmosphere of argon gas. Asolution of t-butyl diethylphosphonoacetate (700 mg) in tetrahydrofuran(15 ml) was added to the suspension. The mixture was stirred for 15 min.at room temperature. A solution of the obtained aldehyde (711 mg) intetrahydrofuran (10 ml) was gradually added to the mixture occasionallywith ice-cooling. The mixture was stirred for 10 min. at roomtemperature. Acetic acid was gradually added to the reaction mixtureuntil pH of the reaction mixture was down to 5.0. The reaction mixturewas gel-filtered with using YMC gel. Moreover the gel was washed withethyl acetate. A mixture of the filtrate and washings was evaporated.The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=1:3) to give the title compound (179 mg) havingthe following physical data.

TLC(n-hexane:ethyl acetate=1:4): Rf 0.49.

Reference Example 10

t-Butyl 3- 1-5-(tetrahydropyran-2-yl)oxy-n-pentyl!oxy-4-(4-N,N-dimethylaminocarbonylbutanamido)benzen-2-yl!propionate##STR62##

The phenol compound (356 mg), which was obtained with using the esterprepared in reference example 3 by the same procedure as referenceexamples 5→reference example 6 (with the proviso that dimethylamine wasused instead of morpholine), was dissolved in dimethyl formamide (5 ml).The solution was ice-cooled. Sodium hydride (content:62%; 22.6 mg) wasadded to the solution. This solution was stirred for 15 minutes at roomtemperature. A solution of1-chloro-5-(tetrahydropyran-2-yl)oxy-n-pentane (206 mg) in dimethylformamide (1 ml) was added to the reaction mixture. The mixture wasstirred at 75° C. all night. The reaction mixture was diluted withether. The mixture was washed with water, dried over anhydrous magnesiumsulfate and evaporated. The residue was purified by columnchromatography on silica gel (chloroform:methanol=20:1) to give thetitle compound (336 mg) having the following physical data.

MS: m/z 548 (M⁺), 464.

Reference Example 11

3-1-(5-formyloxy-n-pentyl)oxy-4-(4-N,N-dimethylaminocarbonylbutanamido)benzen-2-yl!propionicacid

The ester (336 mg) prepared in reference example 10 was ##STR63##dissolved in formic acid (5 ml). The solution was stirred for 1 hr. atroom temperature and then for 1 hr. at 45° C. The reaction solution wasevaporated to give the residue contained the title compound having thefollowing physical data. The residue was used in next reaction withoutpurification.

TLC(chloroform:methanol, 10:1):Rf 0.33

Reference Example 12

Methyl3-(1-(5-formyloxy-n-pentyl)oxy-4-(4-N,N-dimethylaminocarbonylbutanamido)benzen-2-yl!propionate##STR64##

The residue which contained the carboxylic acid prepared in referenceexample 11 was dissolved in ethyl acetate (2 ml). A solution ofdiazomethane in ether was added to the solution until the reactionmixture was slightly tinged with yellow. The reaction mixture wasevaporated. The residue was purified by column chromatography on silicagel (chloroform:methanol=20:1) to give the title compound (227 mg)having the following physical data.

MS: m/z 450 (M⁺), 406.

Reference Example 13

Methyl 3-1-(5-hydroxy-n-pentyl)oxy-4-(4-N,N-dimethylaminocarbonylbutanamido)benzen-2-yl!propionate##STR65##

The ester (220 mg) prepared in reference example 12 was dissolved inmethanol (2 ml). Potassium carbonate (82.8 mg) was added to thesolution. The mixture was stirred for 2 hr. at room temperature. Themixture was acidified with 1N hydrochloric acid. The mixture wasextracted with ethyl acetate. The extract was washed with water, driedover anhydrous magnesium sulfate and then evaporated. The residue waspurified by column chromatography on silica gel(chloroform:methanol=20:1) to give the title compound (176 mg) havingthe following physical data.

MS m/z 422(M⁺), 281.

Reference Example 14

Methyl 3-1-(4-formyl-n-butyl)oxy-4-(4-N,N-dimethylaminocarbonylbutanamido)benzen-2-yl!propionate##STR66##

The alcohol (173 mg) prepared in reference example 13 was dissolved indimethyl sulfoxide (2 ml). Triethylamine (207.5 mg) and sulfurtrioxide-pyridine complex (195.6 mg) were added to the solution. Themixture was stirred for 30 min. at room temperature. The reactionsolution was acidified with 1N hydrochloric acid. The solution wasextracted with ether. The extract was washed with water, dried overanhydrous magnesium sulfate and then evaporated. The residue waspurified by column chromatography on silica gel (chloroform:methanol=20:1) to give the title compound (61 mg) having the followingphysical data.

NMR: δ 9.80 (1H, t, J=1 Hz), 8.10 (1H, s), 7.42 (1H, d, d, J=8 Hz, J=1Hz), 7.23 (1H, d, J=1 Hz), 6.75 (1H, d, J=8 Hz), 4.00-3.90 (2H, m), 3.70(3H, s), 3.03 (3H, s), 2.99 (3H, s), 2.92 (2H, t, J=7 Hz), 2.65-2.40(6H, m), 2.15-1.95 (2H, m), 1.90-1.45 (4H, m).

Reference Example 15

Methyl 3-1-(5E-7-oxopentadecenyl)oxy-4-(4-dimethylaminocarbonylbutaneamido)benzene-2-yl!propionate##STR67##

A solution of dimetyl 2-oxodecylphosphonate (132 mg) in tetrahydrofuran(1 ml) was added to a suspension of sodium hydride (content: 62%; 7.75mg) in tetrahydrofuran (3 ml). A solution of the aldehyde (59 mg)prepared in reference example 14 in tetrahydrofuran (2 ml) was added tothe mixture. The solution was stirred for 30 min. at room temperatureand then for 1 hr. at 60° C. The reaction solution was acidified withacetic acid. The solution was gel-filtered. The filtrate was evaporated.The residue was purified by column chromatography on silica gel (ethylacetate methanol=20:1) to give the title compound (50 mg) having thefollowing physical data.

MS: m/z 558 (M⁺), 417.

Reference Example 16

Methyl 3-1-(5E-7-hydroxypentadecenyl)oxy-4-(4-dimethylaminocarbonylbutanamido)benzen-2-yl!propionate##STR68##

The compound (48 mg) prepared in reference example 15 and ceriumchloride 7H₂ O (37.3 mg) were dissolved in methanol (1 ml). Sodiumborohydride (3.25 mg) in limited amounts was added to the solution. Themixture was stirred for 30 min. at room temperature. The reactionsolution was acidified with acetic acid. The solution was extracted withethyl acetate. The extract was washed with water, dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by columnchromatography on silica gel (chloroform:methanol=20:1) to give thetitle compound (46 mg) having the following physical data.

MS: m/z 560, 542.

Reference Example 17

t-Butyl 3-(1-hydroxy-4-trifluoroacetoamidobenzen-2-yl)propionate##STR69##

t-Butyl 3-(1-hydroxy-4-aminobenzen-2-yl)propionate was dissolved in amixture of tetrahydrofuran (100 ml) and triethylamine (7.1 ml).Anhydrous trifluoroacetic acid (6.0 ml) was added to the solution at 0°C. in an atmosphere of argon gas. The solution was stirred for 2 hr. at0° C. The reaction solution was poured into a mixture of ice and 1Nhydrochloric acid (100 ml). The reaction mixture was extracted withethyl acetate (300 ml). The extract was washed with water, saturatedaqueous solution of sodium bicarbonate, followed by brine, dried overanhydrous magnesium sulfate and evaporated. The residue wasrecrystallized from a mixture of ethyl acetate-n-hexane (1:5) to givethe title compound having the following physical data.

TLO(ethyl acetate:n-hexane=1:2):Rf 0.30;

MS m/z 333 (M⁺), 277, 259, 231, 217.

Reference Example 18

t-Butyl 3-(1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-aminobenzen-2-yl!propionate##STR70##

The trifluoroacetoamide (5.3 g), which was prepared with using thecompound prepared in reference example 17 by the same procedure asreference example 4 was dissolved in a mixture of methanol (30 ml) andwater (5 ml). Anhydrous potassium carbonate (2.8 g) was added to thesolution. The mixture was stirred at room temperature a whole day andnight. Water (100 ml) was added to the reaction mixture. The reactionmixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with brine, dried over anhydrous magnesium sulfate and thenevaporated. The residue was purified by column chromatography on silicagel (ethyl acetate:n-hexane=2:3) to give the title compound (3.5 g)having the following physical data.

TLC(ethyl acetate:n-hexane=1:2):Rf 0.20;

MS: m/z 425 (M⁺), 369, 189, 181, 163, 147, 121.

Reference Example 19

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(N-acetyl-N-mesylaminobenzen-2-yl!propionate##STR71##

The ester (176 mg) prepared in reference example 18 was dissolved in amixture of methylene chloride (3 ml) and triethylamine (0.29 ml).Methanesulfonyl chloride (35 μl) was added to the solution at 0° C. Thesolution was stirred for 30 min. Acetyl chloride (0.12 ml) was added tothe reaction solution. The mixture was refluxed for 10 min. The reactionmixture was poured into a mixture of ice and 1N hydrochloric acid (10ml). The reaction mixture was extracted with ethyl acetate (80 ml). Theextract was washed with water, followed by brine, dried over anhydrousmagnesium sulfate and evaporated. The residue was purified by columnchromatography on silica gel (ethyl acetate:) n-hexane=1:2) to give thetitle compound (200 mg) having the following physical data.

TLC(ethyl acetate:n-hexane=1:1):Rf 0.40;

MS: m/z 545 (M⁺), 489, 447, 189, 147, 121.

Reference Example 20

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-dimesylaminobenzene-2-yl!propionate##STR72##

The ester (158 mg) prepared in reference example 18 was dissolved in amixture of methylene chloride (3 ml) and triethylamine (0.15 ml).Methanesulfonyl chloride (72 μl) was added to the solution at roomtemperature. The solution was stirred for 1 hr. The reaction solutionwas poured into a mixture of ice and 1N hydrochloric acid (10 ml). Thereaction mixture was extracted with ethyl acetate (80 ml). The extractwas washed with water, followed by brine, dried over anhydrous magnesiumsulfate and then evaporated. The residue was purified by columnchromatography on silica gel (ethyl acetate:n-hexane=1:2) to give thetitle compound (170 mg) having the following physical data.

TLC(ethyl acetate:n-hexane=1:2):Rf 0.25;

MS: m/z 581 (M⁺), 525, 189, 147, 121.

Reference Example 21

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-phthalimidobenzen-2-yl!propionate##STR73##

The ester (176 mg) prepared in reference example 18 was dissolved inchloroform (5 ml). Anhydrous phthalic acid (120 mg) was added to thesolution. The solution was refluxed for 24 hr. The reaction solution wasevaporated. The residue was purified by column chromatography on silicagel (methylene chloride→methylene chloride:ethyl acetate=10:1) to givethe title compound (130 mg) having the following physical data.

TLO(ethyl acetate: n-hexane=1:4):Rf 0.20;

MS: m/z 555 (M⁺), 499, 311, 293, 189, 147, 121.

Reference Example 22

t-Butyl 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(perhydro-1,2-thiazin-1,1,3-trione-2-yl)benzen-2-yl!propionate##STR74##

The t-butyl ester (950 mg), which was prepared with using the esterprepared in reference example 18 by the same procedure as referenceexample 3 (with the proviso that the corresponding sulfonyl chloride wasused instead of 4-methoxycarbonylbutanoyl chloride)→reference example 5,was dissolved in a mixture of tetrahydrofuran (15 ml) and triethylamine(0.69 ml). Ethyl chloroformate (0.24 ml) was gradually added to thesolution at 15° C. in an atmosphere of argon gas. The solution wasstirred for 10 min at -15° C. and then for 30 min at 0° C. The reactionsolution was poured into a mixture of ice and 1N hydrochloric acid (20ml). The reaction mixture was extracted with ethyl acetate (100 ml). Theextract was washed with water, saturated aqueous solution of sodiumbicarbonate, followed by brine, dried over anhydrous magnesium sulfateand evaporated. The residue was purified by column chromatography onsilica gel (ethyl acetate:) n-hexane=2:1) to give the title compound(710 mg) having the following physical data.

TLC(ethyl acetate:n-hexane=2:1):Rf 0.60;

MS m/z 557 (M⁺), 501, 187, 121.

Reference Example 23

t-Butyl 3- 1-5-hydroxy-n-pentyl)oxy-4-trifluoroacetoamidobenzen-2-yl!propionate##STR75##

The ester (2.56 g), which was prepared with using the ester prepared inreference example 17 by the same procedure as reference example 10, wasdissolved in ethanol. p-Toluenesulfonic acid (15 mg) was added to thesolution. The solution was stirred for 40 min at room temperature. Fewdrops of triethylamine was added to the reaction solution. The reactionmixture was evaporated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:1) to give thetitle compound (1.93 g) having the following physical data.

TLC(ethyl acetate:n-hexane=1:2):Rf 0.10;

MS: m/z 419 (M⁺), 363, 277, 259, 231.

Reference Example 24

3-(1,4-dimethoxybenzen-2-yl)prop-2E-enoic acid ##STR76##

2,5-Dimethoxybenzaldehyde (1.7 g) was dissolved in pyridine (10 ml).Piperidine (0.2 ml) and malonic acid (2.0 g) were added to the solution.The solution was stirred for 1 hour at 85° C. and then for 3 hr. at 110°C. The solution was cooled. Water (80 ml) was added to the solution.Conc. hydrochloric acid was added to the solution until pH of thesolution was down to about 2. The crystals were deposited. The crystalswere separated from the solution by filtration, washed with water anddried to give the title compound (1.97 g) having the following physicaldata.

NMR δ8.08 (1H, d, J=16 Hz), 7.08 (1H, d, J=2 Hz), 6.98-6.83 (2H,m), 6.53(1H, d, J=16 Hz), 3.85 (3H, s), 3.80 (3H, s).

Reference Example 25

6-Hydroxycoumarin ##STR77##

The carboxylic acid (1.97 g; prepared in reference example 24) andpyridine hydrochloride (12 g) were heated to 180-190° C. The mixture wasreacted for 3.5 hr. The reaction mixture was cooled and then dissolvedin water. The solution was extracted with ethyl acetate. The extract waswashed with water, dried over anhydrous magnesium sulfate and thenevaporated. The residue was purified by column chromatography on silicagel (n-hexane:ethyl acetate=3:1→1:1). The obtained crystals were washedwith a mixture of n-hexane and ethyl acetate (3:1→1:1) to give the titlecompound (751 mg) having the following physical data.

NMR: δ 7.67 (1H, d, J=10 Hz), 7.20 (1H, d, J=8 Hz), 7.05 (1H, dd, J=8Hz, J=1 Hz), 6.90 (1H, d, J=1 Hz), 6.40 (1H, d, J=10 Hz).

Reference Example 26

6-(4-ethoxycarbonylbutyl)oxycoumarin ##STR78##

6-Hydroxycoumarin (405 mg; prepared in reference example 25) wasdissolved in dry dimethylformamide (6 ml). Sodium hydride (60 mg) wasadded to the solution. The mixture was reacted for 15 min. Ethyl5-bromopentanoate (0.48 ml) was added dropwise to the reaction solution.The mixture was stirred for 1 hr at 60° C. Ice-water was added to thereaction solution. The mixture was acidified with 1N hydrochloric acid.The mixture was extracted with ether. The extract was washed with water,dried anhydrous magnesium sulfate and then evaporated. The residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=4:1→2:1) to give the title compound (398 mg) having thefollowing physical data.

NMR: 7.75 (1H, d, J=10 Hz), 7.25 (1H, d, J=8 Hz), 7.10 (1H, dd, J=8 Hz,J=1 Hz), 6.90 (1H, d, J=1 Hz), 6.43 (1H, d, J=10 Hz).

Reference Example 27

Ethyl 3- 1-hydroxy-4-(4-ethoxycarbonylbutoxy)benzen-2-yl!prop-2E-enoate##STR79##

Sodium hydride (content: 62%; 60 mg) was gradually added to anhydrousethanol (10 ml) and dissolved. A solution of the ester (314 mg; preparedin reference example 26) in anhydrous ethanol (1 ml) was added to thesolution. The mixture was stirred for 4 hr. at 70° C. and then for 30min at 80° C. Glacial acetic acid (210 mg) was added to the reactionsolution with ice-cooling to stop the reaction. The solvent was removedfrom the reaction solution under reduced pressure. The residue wasdiluted with ether. The mixture was washed with water. Aqueous layer wasremoved. Ethereal layer was dried over anhydrous magnesium sulfate andthen evaporated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=2:1) to give the title compound (122mg) having the following physical data.

TLC(n-hexane:ethyl acetate=2:1):Rf 0.20.

Reference Example 28

Methyl 3- 1-methoxy-4-(1-oxo-⁴-methoxycarbonyl-n-butyl)benzen-2-yl!propionate ##STR80##

Anhydrous aluminium chloride (22.2 g) was suspended in methylenechloride (150 ml). The suspension was cooled to 0° C. Methyl4-(chloroformyl)butylate (10.0 g) was added to the suspension at 0° C.The methyl ester (10.5 g), which was prepared with using3-(1-methoxybenzen-2-yl)propanoic acid (10.0 g) by the same procedure asreference example 12, was added to the prepared suspension. Thesuspension was stirred for 30 min. The reaction solution was poured intoa mixture of ice and 2N hydrochloric acid. The reaction mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and then evaporated. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1→3:2) to give the title compound (13.6 g)having the following physical data.

TLC(n-hexane:ethyl acetate=2:1):Rf 0.33;

MS: m/z 322 (M⁺), 291.

Reference Example 29

3- 1-hydroxy-4-(4-carboxyl-n-butyl)benzen-2-yl!propionic acid ##STR81##

An ester (1.0 g), which was prepared with using the ester prepared inreference example 28 by the same procedure as reference example 16, wasdissolved in dimethylsulfoxide (2 ml). The solution was stirred for 30min. at 180° C. The reaction solution was diluted with ether. Themixture was washed with 1N hydrochloric acid, followed by saturatedbrine, dried over anhydrous magnesium sulfate and then evaporated. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give an olefin compound. The olefincompound (848 mg) was dissolved in ethanol (15 ml). A suspension of 10%palladium-carbon (100 mg) in ethanol (5 ml) was added to the solution.The mixture was stirred for 1.5 hr. at room temperature in an atmosphereof hydrogen gas. The catalyst was removed from the reaction solution byCelite 545. The reaction solution was evaporated to give a reducedcompound (798 mg). Pyridinium chloride (15 g) was added to the reducedcompound (1.66 g). The mixture was stirred for 4 hr. at 180° C. Atemperature of the reaction mixture was down to room temperature. Themixture was dissolved in 1N hydrochloric acid. The reaction mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated to give theresidue contained the title compound having the following physical data.The residue was used in next reaction without purification.

TLC(ethyl acetate):Rf 0.39;

MS: m/z 266 (M⁺), 248, 161.

Reference Example 30

5-(3,4-dihydrocoumarin-6-yl)valeric acid ##STR82##

The dicarboxylic acid (1.72 g) prepared in reference example 29 wasdissolved in a mixture of benzene (100 ml) and tetrahydrofuran (2 ml).Dowex 50W×8 (H⁺ form)(about 10 ml) was added to the solution. Themixture was refluxed for 2 hr. The reaction solution was filtered toremove Dowex. The filtrate was evaporated to give the residue (1.28 g)contained the title compound having the following physical data. Theresidue was used in next reaction without purification.

TLC(chloroform:methanol=10:1):Rf 0.49;

MS: m/z 248 (M⁺), 230.

Reference Example 31

Ethyl 3-1-hydroxy-4-dimethylaminocarbonyl-n-butyl)benzen-2-yl!propionate##STR83## A carboxylic acid, which was prepared with using the lactoneprepared in reference example 30 by the same procedure as referenceexample 6 (with the proviso that dimethylamine was used instead ofmorpholine)→example 5, was dissolved in ethanol (5 ml). Conc. sulfuricacid (about 0.1 ml) was added dropwise to the solution. The solution wasstirred for 1.5 hr. at 60° C. The reaction solution was diluted withethyl acetate. The diluted solution was washed with saturated aqueoussolution of sodium bicarbonate, followed by saturated brine, dried overanhydrous magnesium sulfate and evaporated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate) to give the titlecompound (1.5 g) having the following physical data.

TLC(ethyl acetate):Rf 0.58;

MS: m/z 307 (M⁺), 276.

Reference Example 32

3- 1-hydroxy-4-(1-oxo-4-carboxylbutyl)benzen-2-yl!propionic acid##STR84##

A dicarboxylic acid (6.6 g), which was prepared with using the esterprepared in reference example 28 by the same procedure as referenceexample 5, was dissolved in acetic acid (10 ml). 47% hydrobromic acid(30 ml) was added to the solution. The mixture was refluxed all night.The reaction solution was evaporated. The residue was diluted with ethylacetate. The diluted solution was washed with saturated brine, driedover magnesium sulfate and then evaporate. The residue wasrecrystallized from ethyl acetate to give the title compound (915 mg)having the following physical data.

MS: m/z 280 (M⁺), 262.

Reference Example 33

Anhydrous 4-methoxyphthalide ##STR85##

Anhydrous 2-methoxyphthalic acid (640 mg), which was prepared with usinganhydrous 2-hydroxyphthalic acid by the same procedure as referenceexample 12, was suspended in tetrahydrofuran (20 ml). Acetic acid (430mg) and sodium borohydride (135 mg) were added to the suspension. Themixture was stirred for 30 min. at room temperature and for 2 hr. at 50°C. The reaction solution was cooled. 1N hydrochloric acid (7 ml) wasadded to the cooled solution. The solution was stirred for 15 min. Thereaction solution was evaporated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to givethe title compound (314 mg) having the following physical data.

TLC(n-hexane:ethyl acetate=1:1):Rf 0.67.

Reference Example 34

1-hydroxy-4-methoxy-1,3-dihydrobenzo c!furan ##STR86##

The phthalide (346 mg) prepared in reference example 33 was dissolved intoluene (20 ml). The solution was cooled to -78° C. A 1.76N solution ofdiisobutylaluminum hydride (DIBAL) in toluene (1.43 ml) was addeddropwise to the cooled solution. The mixture was stirred for 30 min. at-78° C. Methanol (0.2 ml) was added to the reaction solution todecompose the excess DIBAL. Water was added to the reaction solution. Atemperature of the solution was up to room temperature. The solution wasstirred for 30 min. at room temperature. The reaction solution was driedover anhydrous sodium sulfate, washed with ethyl acetate and evaporatedto give the residue contained the title compound having the followingphysical data. The residue was used in next reaction withoutpurification.

TLC(n-hexane:ethyl acetate 1:1):Rf 0.56

Reference Example 35

Methyl 5E-6-(2-hydroxymethyl-3-methoxyphenyl)hexenoate ##STR87##

(4-Carboxylbutyl)triphenylphosphonium bromide (2.79 g) was suspended intoluene (30 ml). Potassium t-butoxide (1.34 g) was added to thesuspension. The suspension was stirred for 15 min. at 80° C. A solutionof the compound (348 mg) prepared in reference example 34 in toluene (10ml) was added dropwise to the reaction solution. The solution wasstirred for 1.5 hours at 80° C. The reaction mixture was cooled and thenacidified by adding 1N hydrochloric acid. The solution was extractedwith ethyl acetate. The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated. The residue was purified bycolumn chromatography (n-hexane:ethyl acetate=1:1) to give the titlecompound (270 mg) having the following physical data.

NMR: δ 7.12 (1H, t, J=8 Hz), 7.03 (1H, d, J=8 Hz), 6.85-6.70 (2H, m),6.05 (1H, d, t, J=16 Hz, J=6 Hz), 4.80 (2H, s), 3.90 (3H, s);

MS: m/z 250 (M⁺), 232.

Reference Example 36

Ethyl 6- 2-(2-ethoxycarbonylethyl)-3-hydroxyphenyl!hexanoate ##STR88##

Methyl 6- 2-(2-ethoxycarbonylethyl)-3-methoxyphenyl!-hexanoate, whichwas prepared with using the compound prepared in reference example 35 bythe same procedure as reference example 12→reference example 2→referenceexample 14→reference example 1 (with the proviso that ethyldiethylphosphonoacetate was used instead of t-butyldiethylphosphonoacetate)→reference example 2, and pyridine hydrochloridewere reacted for 2 hr. at 190° C. The reaction mixture was cooled. 1Nhydrochloric acid was added to the mixture. The mixture was extractedwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate and then evaporated. The residue was dissolved in a saturatedsolution of hydrogen chloride in ethanol (5 ml). The solution wasstirred for 30 min. The reaction solution was evaporated. The residuewas purified by column chromatography on silica gel (n-hexane:ethylacetate=2:1) to give the title compound (87.3 mg) having the followingphysical data.

NMR δ 7.13 (1H, d, J=8 Hz), 7.03 (1H, t, J=8 Hz), 6.75 (2H, d, J=8 Hz),4.20-4.05 (4H, m), 2.93 (2H, t, J=7 Hz), 2.70-2.50 (4H, m), 2.30 (2H, t,J=7 Hz), 1.75-1.30 (6H, m), 1.30-1.20 (6H, m);

MS: m/z 336 (M⁺), 291, 262.

Reference Example 37

Methyl 2E-3-(2-hydroxymethyl-6-methoxyphenyl)acrylate ##STR89##

1Hydroxy-7-methoxy-1,3-dihydrobenzo c!furan (1.08 g), which was preparedwith using 7-methoxyphthalide which was synthesized with using3-methoxybenzaldehyde by the method described in Journal of OrganicChemistry, 1980, 45, 1835-1838, was dissolved in Chloroform (20 ml).Methyl (Triphenylphosphoranylidene)acetate (2.68 g) was added to thesolution. The mixture was stirred for 40 min. at 50° C. A temperature ofthe reaction mixture was down to room temperature. The reaction solutionwas purified by column chromatography on silica gel (n-hexane:ethylacetate=2:1) to give the title compound (1.25 g) having the followingphysical data.

NMR: δ 8.93 (1H, d, J=16 Hz), 7.30 (1h, t, J=8 Hz), 7.07 (1H, d, J=8Hz), 6.90 (1H, d, J=8 Hz), 6.70 (1, d, J=16 Hz, 4.80 (2H, d, J=5 Hz),3.87 (3H, s), 3.81 (3H, s);

MS: m/z 222 (M⁺), 204, 191.

Reference Example 38

Methyl 3- 2-(1-hydroxyhex-5-enyl)-6-methoxyphenyl!propionate ##STR90##

5-Bromo-1-penten (596 mg) was added dropwise to a solution of magnesium(96 mg) in diethyl ether (2 ml). Diethyl ether (4 ml) was added to thesolution to prepare Grignard reagent. A solution of methyl3-(2-formyl-6-methoxyphenyl)propionate (444 mg), which was prepared withusing the ester prepared in reference example 37 by the same procedureas reference example 2→reference example 14, in diethyl ether (1 ml) wasice-cooled. The grignard reagent (3.3 ml) prepared beforehand was addeddropwise to the cooled solution. The mixture was stirred for 1.5 hr.with ice-cooling. The reaction mixture was added to a saturated aqueoussolution of ammonium chloride. The mixture was extracted with diethylether. The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=4:1) to give thetitle compound (497.5 ) having the following physical data.

NMR; δ 7.23 (1H, t, J=8 Hz), 7.10 (1H, d, J=8 Hz), 6.78 (1H, d J=8 Hz)6.90-6.70 (1H, m), 5.06-4.90 (3H, m), 3.85 (3H, s), 3.67 (3H, s),3.05-2.95 (2H, m), 2.65-2.52 (2H, m), 2.15-2.05 (2H, m), 1.90-1.35 (4H,m);

MS: m/z 292 (M⁺), 260, 243.

Reference Example 39

Methyl 3- 2-(1,6-dihydroxyhexyl)-6-methoxyphenyl!propionate ##STR91## Asolution of the ester (494.5 mg) prepared in reference example 38 intetrahydrofuran (6.77 ml) was ice-cooled. A 1N solution (6.77 ml) ofdiborane in tetrahydrofuran was added dropwise to the solution. Themixture was stirred for 30 min at room temperature. The reactionsolution was ice-cooled. Water was added dropwise to the solution todecompose excess diborane. A 1N aqueous solution of sodium hydroxide andthen 30% hydrogen peroxide (6.77 ml) were added dropwised to thereaction mixture. The mixture was stirred for 30 min. at roomtemperature and reacted by the same procedure as reference example 12.The reaction solution was poured into a 1N solution of hydrochloric acidin diethyl ether (100 ml). The mixture was extracted with diethyl ether.The extract was washed with water, dried over anhydrous magnesiumsulfate and then evaporated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to givethe title compound having the following physical data.

NMR: δ 7.23 (1H, t, J=8 Hz), 7.08 (1H, d, J=8 Hz), 6.78 (1H, d, J=8 Hz),5.05-4.95 (1H, m), 3.83 (3H, s), 3.67 (3H, s), 3.63 (2H, t, J=7 Hz),3.05-2.95 (2H, m), 2.65-2.53 (2H, m), 1.90-1.30 (8H, m);

MS: m/z 310 (M⁺), 223.

Reference Example 40

6-Oxo-6- 2-(2-methoxycarbonylethyl)-3-methoxyphenyl!hexanoic acid##STR92##

A solution of6-oxo-6-(2-(2-methoxycarbonylethyl)-3-methoxyphenyl!hexanal (450 mg),which was prepared with using the ester prepared in reference example 39by the same procedure as reference example 14, in acetone (6 ml) wasice-cooled. 2.67N Jone's reagent (2 ml) was added dropwise to thesolution. The mixture was stirred for 1 hr. with ice-cooling. Isopropylalcohol was added to the solution to stop the reaction. Water was addedto the solution to dissolve chromic anhydride. The reaction mixture wasextracted with diethyl ether. The extract was washed with water, driedover anhydrous magnesium sulfate and then evaporated. The residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=2:1→1:1) to give the title compound (369 mg) having thefollowing physical data.

NMR: δ 8 7.25 (1H, t, J=8 Hz), 7.08 (1H, d. J=8 Hz), 6.95 (1H, d, J=8Hz), 3.85 (3H, s), 3.67 (3H, s), 3.05-2.95 (4H, m), 2.67-2.55 (2H, m),2.40 (2H, t, J=7 Hz), 1.85-1.60 (4H, m)

Example 1

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(5-oxo-5-morpholinopentanamido)benzen-2-yl!propionicacid ##STR93##

The butyl ester (70 mg; prepared in reference example 6) was dissolvedin formic acid (5 ml). The solution was stirred for 5 hr. at roomtemperature. The reaction solution was evaporated to remove formic acid.The residue was purified by column chromatography on silica gel (ethylacetate:methanol=10:1) to give the title compound (40 mg) of the presentinvention, having the following physical data.

TLC(ethyl acetate:methanol=10:1):Rf 0.10;

IR(cm⁻¹): ν 3307, 2932, 1723, 1609, 1510, 1245, 1116, 1032.

Example 1(a)-1(v)

The compounds, of the present invention, shown in the following table 4were obtained, with using the compounds which were prepared with usingthe butyl ester prepared in reference example 5 and the correspondingamines by the same procedure as reference example 6 (with the provisothat the corresponding amines were used instead of morpholine) or thecompounds which were prepared with using the corresponding appropriatecompounds shown in the formula MsO-Z¹ -B¹ or Br-Z² -B² (wherein all ofthe symbols are the same meaning as described hereinbefore) by the sameprocedure as reference example 4, 5 and 6 (with the proviso that thecorresponding amines were used instead of morpholine), by the sameprocedure as example 1.

                                      TABLE 4                                     __________________________________________________________________________    Ex. No.                                                                           Structural formula                    TLC      IR (cm.sup.-1)             __________________________________________________________________________    1(a)                                                                               ##STR94##                            Rf 0.31 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3357, 2952, 1715,                                                        1683, 1602, 1542,                                                             1508, 1471, 1410,                                                             1235, 1176, 1117,                                                             1031, 972, 886, 825        1(b)                                                                               ##STR95##                            Rf 0.37 (ethyl acetate:                                                       methanol = 5:1)                                                                        ν 3333, 2940, 1704,                                                        1687, 1608, 1554,                                                             1505, 1474, 1422,                                                             1277, 1222, 1200,                                                             1124, 1029, 805            1(c)                                                                               ##STR96##                            Rf 0.52 (ethyl acetate:                                                       methanol = 5:1)                                                                        ν 3315, 2923, 2849,                                                        1687, 1607, 1553,                                                             1505, 1473, 1422,                                                             1224, 811                  1(d)                                                                               ##STR97##                            Rf 0.53 (ethyl acetate:                                                       methanol = 5:1)                                                                        ν 3270, 2918, 2850,                                                        1712, 1650, 1605,                                                             1539, 1504, 1473,                                                             1415, 1230, 1116,                                                             1031, 805, 718             1(e)                                                                               ##STR98##                            Rf 0.30 (chloroform: methanol =                                               10:1)    ν 1634, 1506, 1242,                                                        048, 977, 810              1(f)                                                                               ##STR99##                            Rf 0.28 (chloroform: methanol =                                               10:1)    ν 2937, 1715, 1607,                                                        1550 1505, 1472, 1422,                                                        1240, 1176, 1119,                                                             1023, 969, 810, 756        1(g)                                                                               ##STR100##                           Rf 0.30 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3273, 2932, 2855,                                                        2837, 1711, 1650,                                                             1601, 1540, 1511,                                                             1406, 1416, 1348,                                                             1248, 1229, 1178,                                                             1116, 1034, 971, 805       1(h)                                                                               ##STR101##                           Rf 0.30 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3284, 3067, 2927,                                                        2854, 1735, 1711,                                                             1650, 1624, 1600,                                                             1561, 1511, 1468,                                                             1416, 1246, 1172,                                                             1117, 1033, 805            1(i)                                                                               ##STR102##                           Rf 0.27 (chloroform: methanol =                                               10:1)    ν 3305, 2933, 1728,                                                        1608, 1550, 1504,                                                             1471, 1242, 1175,                                                             1119, 1051, 968, 810,                                                         756                        1(j)                                                                               ##STR103##                           Rf 0.49 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3304, 2933, 2857,                                                        1727, 1613, 1549,                                                             1512, 1504, 1469,                                                             1419, 1245, 1178,                                                             1118, 1036, 883, 813,                                                         753                        1(k)                                                                               ##STR104##                           Rf 0.49 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3276, 2933, 1710,                                                        1648, 1600, 1539,                                                             1503, 1414, 1347,                                                             1258, 1228, 1116,                                                             1058, 968, 883, 805,                                                          694                        1(l)                                                                               ##STR105##                           Rf 0.34 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3300, 2937, 1719,                                                        1616, 1549, 1503,                                                             1467, 1438, 1420,                                                             1242, 1162, 1118,                                                             1051, 1029, 976, 884,                                                         814                        1(m)                                                                               ##STR106##                           Rf 0.39 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3301, 3008, 2938,                                                        1723, 1607, 1549,                                                             1503, 1471, 1453,                                                             1423, 1236, 1156,                                                             1119, 1047, 971, 881,                                                         813, 756                   1(n)                                                                               ##STR107##                           Rf 0.50 (ethyl acetate:                                                       methanol = 10:1)                                                                       ν 2936, 1273, 1655,                                                        1510, 1484, 1420,                                                             1246                       1(o)                                                                               ##STR108##                           Rf 0.40 (ethyl acetate:                                                       methanol = 10:1)                                                                       ν 3273, 2933, 1691,                                                        1646, 1551, 1511,                                                             1248                       1(p)                                                                               ##STR109##                           Rf 0.55 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3295, 3262, 2936,                                                        1695, 1676, 1609,                                                             1552, 1511, 1501,                                                             1474, 1275, 1245,                                                             1116, 1031, 972, 882,                                                         842, 816                   1(q)                                                                               ##STR110##                           Rf 0.29 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3283, 3120, 2934,                                                        2864, 1732, 1650,                                                             1623, 1526, 1500,                                                             1475, 1459, 1439,                                                             1416, 1347, 1233,                                                             1175, 1117, 969, 802.      1(r)                                                                               ##STR111##                           Rf 0.24 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3303, 3010, 2936,                                                        1770, 1725, 1625,                                                             1549, 1514, 1501,                                                             1467, 1418, 1262,                                                             1236, 1140, 1119,                                                             1027, 755                  1(s)                                                                               ##STR112##                           Rf 0.36 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3301, 3011, 2937,                                                        2869, 1723, 1616,                                                             1549, 1504, 1472,                                                             1414, 1235, 1119,                                                             1043, 969, 813, 756        1(t)                                                                               ##STR113##                           Rf 0.40 (ethyl acetate:                                                       methanol = 6:1)                                                                        ν 3300, 3011, 2937,                                                        1714, 1615, 1549,                                                             1503, 1472, 1405,                                                             1234, 1119, 1091,                                                             1013, 969, 811, 756        1(u)                                                                               ##STR114##                           Rf 0.40 (ethyl acetate:                                                       methanol = 10:1)                                                                       ν 3350, 2934, 1724,                                                        1611, 1510,                __________________________________________________________________________                                                       1249                   

Example 2

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-carboxylbutanamido)benzen-2-yl!propionicacid ##STR115##

The title compound, of the present invention, having the followingphysical data was obtained with using the ester prepared in referenceexample 5 by the same procedure as example 1.

TLC(chloroform:methanol:acetic acid=17:2:1):Rf 0.70;

IR(cm⁻¹): ν 3276, 2932, 1702, 1650, 1609, 1541, 1512, 1245, 1223.

Example 2(a) and 2(b)

The compounds, of the present invention, shown in the following table 5were obtained, with using a tert-butyl ester, which was prepared withusing the ester prepared in reference example 9 by the same procedure asreference example 4→reference example 5, for example 2(a), and atert-butyl ester, which was prepared with using the compound prepared inreference example 2 by the same procedure as reference example 3 (withthe proviso that 3-carboxylbenzoyl chloride was used instead of4-methoxycarbonylbutanoylchloride)→reference example 4→reference example5, for example 2(b), by the same procedure as example 2.

                                      TABLE 5                                     __________________________________________________________________________    Ex. No.                                                                           Structural formula          TLC       IR (cm.sup.-1)                      __________________________________________________________________________    2(a)                                                                               ##STR116##                 Rf 0.40 (chloroform: methanol                                                           ν 3294, 2935, 1699, 1665,                                                  1626, 1513, 1418, 1247, 962         2(b)                                                                               ##STR117##                 Rf 0.70 (chloroform: methanol                                                           ν 3281, 2935, 1702, 1643,                                                  1608, 1536, 1510,                   __________________________________________________________________________                                              1247                            

Example 3

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-heptanamidobenzen-2-yl!propionicacid ##STR118##

The title compound of the present invention, having the followingphysical data, was obtained with using the compound, which was preparedwith using the ester prepared in reference example 2 by the sameprocedure as reference example 3 (with the proviso that heptanoylchloride was used instead of methyl 4-(chloroformyl)butyrate)→referenceexample 4, by the same procedure as example 1.

TLC(ethyl acetate):Rf 0.40;

IR(cm⁻¹): ν 3436, 3269, 2934, 2872, 1732, 1607, 1559, 1512, 1252.

Example 3(a)-3(c)

The compounds, of the present invention, shown in the following table 6was obtained with using the corresponding acyl halide instead ofheptanoyl chloride by the same procedure as example 3.

                                      TABLE 6                                     __________________________________________________________________________    Ex. No.                                                                           Structural formula          TLC       IR (cm.sup.-1)                      __________________________________________________________________________    3(a)                                                                               ##STR119##                 Rf 0.60 (ethyl acetate)                                                                 ν 3277, 2935, 1698, 1643,                                                  1608, 1533, 1510, 1248              3(b)                                                                               ##STR120##                 Rf 0.50 (ethyl acetate)                                                                 ν 3281, 2922, 2852, 1698,                                                  1651, 1609, 1541, 1511, 1250        3(c)                                                                               ##STR121##                 Rf 0.40 (ethyl acetate: methanol =                                                      ν 3326, 2940, 1709, 1636,                                                  1609, 1561, 1510,                   __________________________________________________________________________                                              1248                            

Example 4

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(5-hydroxypentanamido)benzen-2-yl!propionicacid ##STR122##

The title compound, of the present invention, having the followingphysical data was obtained with using the ester prepared in referenceexample 7 by the same procedure as example 1.

TLC(ethyl acetate:methanol=7:1):Rf 0.50;

MS: m/z 469(M⁺), 369, 189, 163, 147, 121.

Example 4(a) and 4(b)

The compounds, of the present invention, shown in the following table 7were obtained, with using a tert-butyl ester, which was prepared withusing the tert-butyl ester prepared in reference example 2 by the sameprocedure as reference example 3 (with the proviso that thecorresponding appropriate reagents were used instead of4-methoxycarbonylbutanoyl chloride)→reference example 4→referenceexample 5→reference example 7, by the same procedure example 4.

                                      TABLE 7                                     __________________________________________________________________________    Ex. No.                                                                           Structural formula                TLC    IR (cm.sup.-1)                   __________________________________________________________________________    4 (a)                                                                              ##STR123##                       Rf 0.67 (ethyl acetate: methanol =                                            6:1)   ν 3288, 2944, 2837, 2529,                                                  698, 1663, 1607, 1555, 1509,                                                  1473, 1443, 1339, 1278,                                                       1246, 1235, 1176, 1159,                                                       1111, 1033, 971, 834             4 (b)                                                                              ##STR124##                       Rf 0.50 (ethyl acetate: methanol =                                            10:1)  ν 3368, 2932, 1731, 1642,                                                  607, 1541, 1508, 1245, 1176,                                                  1033                             __________________________________________________________________________

Example 5

3-1-(5E-7-hydroxypentadecenyl)oxy-4-(4-dimethylamino-carbonylbutanamido)benzen-2-yl!propionicacid ##STR125##

The title compound, of the present invention, having the followingphysical data was obtained with using the methyl ester prepared inreference example 16 by the same procedure as reference example 5.

TLC(chloroform:methanol=10:1):Rf 0.29;

IR(cm⁻¹): ν 3306, 2928, 2856, 1712, 1626, 1552, 1504, 1470, 1414, 1235,1119, 1051, 972, 812.

Example 5(a)-5(e)

The compounds, of the present invention, shown in the following table 8were obtained with using the compounds, which were prepared with usingthe corresponding appropriate reagent by the same procedure as the stepsfor the preparation of the compound of reference example 16, by the sameprocedure as example 5.

                                      TABLE 8                                     __________________________________________________________________________    Ex. No.                                                                           Structural formula                TLC   IR (cm.sup.-1)                    __________________________________________________________________________    5 (a)                                                                              ##STR126##                       Rf 0.35 (chloroform: methanol =                                               10:1) ν 532 (M.sup.+)  514, 391      5 (b)                                                                              ##STR127##                       Rf 0.29 (chloroform: methanol =                                               10:1) ν 3304, 2932, 2859, 1718,                                                  1626, 1551, 1504, 1471, 1407,                                                 1235, 1119, 1052, 972, 912,                                                   885, 813, 733                     5 (c)                                                                              ##STR128##                       Rf 0.28 (chloroform: methanol =                                               10:1) ν 3305, 2937, 2863, 1718,                                                  1614, 1549, 1512, 1504, 1471,                                                 1419, 1246, 1179, 1119, 1038,                                                 973, 815, 755, 666                5 (d)                                                                              ##STR129##                       Rf 0.28 (chloroform: methanol =                                               10:1) ν 3305, 2934, 2874, 1723,                                                  1658, 1615, 1550, 1504, 1471,                                                 1416, 1235, 1119, 1049, 972,                                                  813, 733                          5 (e)                                                                              ##STR130##                       Rf 0.28 (chloroform: methanol =                                               10:1) ν 3305, 2927, 2854, 1714,                                                  1626, 1551, 1504, 1473, 1450,                                                 1417, 1235, 1119, 1044, 974,                                                  913, 892, 813,                    __________________________________________________________________________                                                733                           

Example 6

3- 1-6-(4-methoxyphenyl)hexyl!oxy-4-(4-methylphenyl)-sulfonylaminobenzen-2-yl!propionicacid ##STR131##

The title compound, of the present invention, having the followingphysical data was obtained with using a tert-butyl ester, which wasprepared with using the tert-butyl ester prepared in reference example17 by the same procedure as reference example 4 (with the proviso thatthe corresponding appropriate methanesulfonate was used instead of6-(p-methoxyphenyl)-5E-hexenol methanesulfonate)→reference example18→reference example 3 (with the proviso that the correspondingappropriate sulfonyl chloride was used instead of4-methoxycarbonylbutanoyl chloride), by the same procedure as example 1.

TLC(ethyl acetate:n-hexane=2:1):Rf 0.40;

IR(cm⁻¹): ν 3256, 2932, 2857, 1714, 1612, 1505, 1471, 1396, 1245, 1158,1037, 815, 667.

Example 6(a)-6(c)

The compounds, of the present invention, shown in the following table 9were obtained by the same procedure as example 6.

                                      TABLE 9                                     __________________________________________________________________________    Ex. No.                                                                           Structural formula         TLC    IR (cm.sup.-1)                          __________________________________________________________________________    6 (a)                                                                              ##STR132##                Rf 0.30 (ethyl acetate: n-hexane =                                                   ν 3264, 2936, 1708, 1608, 1511,                                            1248, 1160                              6 (b)                                                                              ##STR133##                Rf 0.30 (ethyl acetate)                                                              ν 3259, 2935, 1697, 1511, 1311,                                            1249, 1225, 1152                        6 (c)                                                                              ##STR134##                Rf 0.30 (ethyl acetate: n-hexane =                                                   ν 3247, 2935, 1708, 1510, 1247,                                            1154                                    __________________________________________________________________________

Example 7

3- 1-6-(4-methoxyphenyl)hexyl!oxy-4-(3-dimethylaminocarbonyl-n-propyl)sulfonylaminobenzen-2-yl!propionicacid ##STR135##

The title compound, of the present invention, having the followingphysical data was obtained with using the phenol compound (prepared inreference example 1) by the same procedure as reference example 4 (withthe proviso that the corresponding appropriate methanesulfonate was usedinstead of 6-(p-methoxyphenyl)-5E-hexenol methanesulfonate)→referenceexample 2→reference example 3 (with the proviso that the correspondingappropriate sulfonyl chloride was used instead of4-methoxycarbonylbutanoyl chloride)→reference example 5→referenceexample 6→example 1.

TLC(ethyl acetate):Rf 0.10;

IR(cm⁻¹): ν 2933, 1693, 1621, 1512, 1247, 1207, 1148.

Example 7(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-dimethylaminocarbonyl-n-propyl)sulfonylaminobenzen-2-yl!propionicacid ##STR136##

The title compound, of the present invention, having the followingphysical data was obtained by the same procedure as example 7.

TLC(ethyl acetate:methanol=10:1):Rf 0.30;

IR(cm⁻¹): ν 2937, 1732, 1615, 1505, 1246, 1152, 1034.

Example 8

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-carboxylpropyl)sulfonylaminobenzen-2-yl!propionicacid ##STR137##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 18 by the same procedure as reference example3→reference example 5→example 1.

TLC(ethyl acetate:methanol=9:1):Rf 0.10;

IR(cm⁻¹): ν 3270, 2932, 1713, 1608, 1504, 1470, 1299, 1153.

Example 9

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(N-acetyl-N-mesyl)-aminobenzen-2-yl!propionicacid ##STR138##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 19 by the same procedure as example 1.

TLC(ethyl acetate):Rf 0.30;

IR(cm⁻¹) ν 2937, 1707, 1511, 1500, 1353, 1246, 1163.

Example 10

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-dimesylaminobenzen-2-yl!propionicacid ##STR139##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 20 by the same procedure as example 1.

TLC(ethyl acetate:n-hexane=2:1):Rf 0.25;

IR(cm⁻¹): ν 2936, 1708, 1607, 1511, 1368, 1248, 1161.

Example 10(a)-10(c)

The compounds, of the present invention, shown in the following table 10were obtained with using tert-butyl esters, which were prepared withusing the ester prepared in reference example 18 by the same procedureas reference example 20 (with the proviso that the correspondingappropriate sulfonyl chloride was used instead of methanesulfonylchloride), by the same procedure as example 10.

                                      TABLE 10                                    __________________________________________________________________________    Ex. No.                                                                           Structural formula         TLC    IR (cm.sup.-1)                          __________________________________________________________________________    10 (a)                                                                             ##STR140##                Rf 0.30 (ethyl acetate: n-hexane =                                                   ν 2934, 1709, 1607, 1511, 1499,                                            1377, 1249, 1168, 662, 549              10 (b)                                                                             ##STR141##                Rf 0.40 (ethyl acetate: n-hexane =                                                   ν 2961, 1714, 1607, 1504, 1470,                                            1380, 1036, 914, 865                    10 (c)                                                                             ##STR142##                Rf 0.40 (ethyl acetate: n-hexane =                                                   ν 2932, 1708, 1607, 1511, 1498,                                            1374, 1352, 1249, 1158                  __________________________________________________________________________

Example 11

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-phthalimidobenzen-2-yl!propionicacid ##STR143##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 21 by the same procedure as example 1.

MS : m/z 499 (M⁺), 293, 265, 189, 147, 121;

IR(cm⁻¹): ν 3215, 2935, 1756, 1702. 1511, 1256, 1150, 1122, 725.

Example 12

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(perhydro-1,2-thiazin-1,1,3-trione-2-yl!benzen-2-yl!propionicacid ##STR144##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 22 by the same procedure as example 1.

TLC(ethyl acetate:methanol=10.1):Rf 0.40;

IR(cm⁻¹): ν 2935, 1718, 1697, 1511, 1500, 1333, 1248, 1151, 1120, 1025.

Example 12(a) and 12(b)

The compounds, of the present invention, shown in the following table 11were obtained with using the compounds, which were prepared with usingthe corresponding appropriate reagents by the same procedure as thesteps for the preparation of the compound of reference example 22, bythe same procedure as example 12.

                                      TABLE 11                                    __________________________________________________________________________    Ex. No.                                                                           Structural formula           TLC    IR (cm.sup.-1)                        __________________________________________________________________________    12 (a)                                                                             ##STR145##                  Rf 0.20 (ethyl acetate)                                                              ν 2933, 1717, 1696, 1513,                                                  1500, 1333, 1249, 1152, 1121,                                                 1026, 821, 529                        12 (b)                                                                             ##STR146##                  Rf 0.40 (ethyl acetate: methanol =                                                   ν 3362, 1729, 1510, 1323,                                                  1250, 1159                            __________________________________________________________________________

Example 13

3-1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(perhydro-1,2-thiazin-1,1,3-trione-2-yl)benzen-2-yl!propionicacid ##STR147##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 23 by the same procedure as reference example14→reference example 15→reference example 16→reference example18→reference example 3 (with the proviso that the correspondingappropriate sulfonyl chloride was used instead of4-methoxycarbonylbutanoyl chloride)→reference example 5→referenceexample 22→reference example 11→reference example 13.

TLC(ethyl acetate:methanol=9:1):Rf 0.50;

MS: m/z 537 (M⁺), 519, 424, 406, 369, 342, 313, 295.

Example 14

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-carboxylbutoxy)benzen-2-yl!propionicacid ##STR148##

The title compound, of the present invention, having the followingphysical data was obtained with using the ethyl ester prepared inreference example 27 by the same procedure as reference example2→reference example 4→reference example 5 and then purification bycolumn chromatography on silica gel.

TLC(chloroform:methanol=10:1):Rf 0.35;

IR(cm⁻¹): ν 2938, 1669, 1606, 1510, 1474, 1426, 1289, 1246, 1227, 1178,1109, 1053, 968, 847, 805.

Example 15

3-1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(4-carboxylbutyl)-oxybenzen-2-yl!propionicacid ##STR149##

The title compound, of the present invention, having the followingphysical data was obtained with using the ethyl ester prepared inreference example 27 by the same procedure as reference example2→reference example 10→reference example 23→reference example14→reference example 15→reference example 16→reference example 5 andthen purification by column chromatography on silica gel.

TLC(chloroform:methanol):Rf 0.36;

IR(cm⁻¹): ν 2926, 2852, 1696, 1508, 1466, 1278, 1229, 1168, 1108, 1070,972, 873, 810.

Example 15(a)-15(c)

The compounds, of the present invention, shown in the following table 12were obtained with using 6-hydroxycoumarin prepared in reference example25 by the same procedure as reference example 26 (with the proviso thatthe corresponding appropriate esters were used instead of ethyl5-bromopentanoate in example 15(b) and 15(c))→reference example27→reference example 2→reference example 10→reference example23→reference example 14→reference example 15 (with the proviso that thecorresponding appropriate phosphonate was used instead of dimethyl2-oxodecylphosphonate for example 15(a))→reference example 16→referenceexample 5 and then purification by column chromatography on silica gel.

                                      TABLE 12                                    __________________________________________________________________________    Ex. No.                                                                           Structural formula                TLC    IR (cm.sup.-1)                   __________________________________________________________________________    15 (a)                                                                             ##STR150##                       Rf 0.26 (chloroform: methanol =                                               10:1)  ν 2937, 1709, 1612, 1586,                                                  513, 1501, 1470, 1246, 1221,                                                  1178, 1038, 974, 810, 758        15 (b)                                                                             ##STR151##                       Rf 0.25 (chloroform: methanol =                                               10:1)  ν 3531, 2925, 2852, 1694,                                                  507, 1466, 1426, 1406, 1393,                                                  1300, 1258, 1228, 1208,                                                       1167, 1110, 1060, 1022, 977,                                                  897, 868, 816, 807, 712          15 (c)                                                                             ##STR152##                       Rf 0.09 (chloroform: methanol =                                               10:1)  ν 3419, 3138, 2926, 2853,                                                  725, 1594, 1500, 1441, 1420,                                                  1404, 1253, 1222, 1181,                                                       1123, 1090, 978, 952, 879,                                                    777                              __________________________________________________________________________

Example 16

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-dimethylaminocarbonyl-n-butyl)oxybenzen-2-yl!propionicacid ##STR153##

The title compound, of the present invention, having the followingphysical data was obtained with using 6-hydroxycoumarin prepared inreference example 25 by the same procedure as reference example 26 (withthe proviso that N,N-dimethyl-5-bromopentanamide was used instead ofethyl 5-bromopentanoate)→reference example 27→reference example2→reference example 4→reference example 5 and then purification bycolumn chromatography on silica gel.

TLC(chloroform:methanol=10:1):Rf 0.56;

IR (cm⁻¹): ν 2937, 1728, 1609, 1510, 1411, 1402, 1247, 1220, 1176, 1121,1036, 969, 846, 803, 756.

Example 16(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-dimethylaminocarbonyl-n-propyl)oxybenzen-2-yl!propionicacid ##STR154##

The title compound, of the present invention, having the followingphysical data was obtained with using 6-hydroxycoumarin prepared inreference example 25 by the same procedure as example 16 (with theproviso that N,N-dimethyl-4-bromobutanamide was used instead ofN,N-dimethyl-5-bromopentanamide).

TLC(ethyl acetate):Rf 0.42;

IR(cm⁻¹): ν 2935, 1729, 1608, 1505, 1471, 1246, 1219, 1176, 1121, 1038,969, 847, 803.

Example 17

3- 1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionic acid ##STR155##

The title compound, of the present invention, having the followingphysical data was obtained with using 6-hydroxycoumarin prepared inreference example 25 by the same procedure as reference example 26 (withthe proviso that N,N-dimethyl-5-bromopentanamide was used instead ofethyl 5-bromopentanoate)→reference example 27→reference example2→reference example 10→reference example 23→reference example14→reference example 15→reference example 16→reference example 5 andthen purification by column chromatography on silica gel.

TLC(chloroform:methanol=10:1):Rf 0.42;

IR(cm⁻¹): ν 3402, 2928, 2857, 1727, 1626, 1500, 1470, 1402, 1220, 1158,1058, 972, 804.

Example 17(a) and 17(b) Example 17(a)

3-1-(5E,9Z-7-hydroxy-n-pentadecadienyl)oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid ##STR156##

Example 17(b)

3-1-(5E-6-methyl-7-hydroxy-n-pentadecenyl)oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid ##STR157##

The title compound, of the present invention, having the followingphysical data was obtained with using 6-hydroxycoumarin prepared inreference example 25 by the same procedure as example 17 (with theproviso that the corresponding appropriate phosphonate was used insteadof dimethyl 2-oxodecylphosphonate for the same procedure as referenceexample 15).

17(a)

TLC(chloroform:methanol=10:1):Rf 0.46;

IR(cm⁻¹): ν 2931, 2860, 1727, 1626, 1500, 1470, 1402, 1220, 1158, 1055,804.

17(b):

TLC(chloroform:methanol=10:1):Rf 0.51;

IR(cm⁻¹): ν 2928, 2857, 1728, 1627, 1500, 1471, 1401, 1220, 1159, 1057,804.

Example 18

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-dimethylaminocarbonylbutyl)benzen-2-yl!propionicacid ##STR158##

The title compound, of the present invention, having the followingphysical data was obtained with using the ester in reference example 31by the same procedure as reference example 4→reference example 5 andthen purification by column chromatography on silica gel.

TLC(ethyl acetate):Rf 0.50;

IR(cm⁻¹): ν 2935, 2861, 1729, 1609, 1510, 1468, 1402, 1249, 1176, 1121,1036, 969, 846, 809.

Example 18(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(5-dimethylaminocarbonylpentyl)benzen-2-yl!propionicacid ##STR159##

The title compound, of the present invention, having the followingphysical data was obtained with using an ester, which was prepared withusing 3-(1-methoxybenzen-2-yl)propionic acid by the same procedure asreference example 12→reference example 28 (with the proviso that methyl5-(chloroformyl)pentanoate was used instead of methyl4-(chloroformyl)butyrate)→reference example 16→reference example29→reference example 30→reference example 31, by the same procedure asexample 18.

TLC(ethyl acetate:methanol=10:1):Rf 0.65;

IR(cm⁻¹) ν 2933, 2857, 1728, 1609, 1511, 1467, 1402, 1290, 1249, 1176,1121, 1035, 968, 846, 809, 756.

Example 19

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-oxo-4-dimethylaminocarbonylbutyl)benzen-2-yl!propionicacid ##STR160##

The title compound, of the present invention, having the followingphysical data was obtained with using the dicarboxylic acid prepared inreference example 32 by the same procedure as reference example30→reference example 27→reference example 2→reference example6→reference example 4→reference example 5 and then purification bycolumn chromatography on silica gel.

TLC(ethyl acetate:methanol=9:1):Rf 0.56;

IR(cm⁻¹) ν 3448, 2941, 2871, 2519, 1736, 1714, 1674, 1603, 1512, 1470,1411, 1362, 1334, 1299, 1282, 1254, 1176, 1160, 1126, 1106, 1035.

Example 19(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-oxo-5-dimethylaminocarbonylpentyl!benzen-2-yl!propionicacid ##STR161##

The title compound, of the present invention, having the followingphysical data was obtained with using a dicarboxylic acid, which wasprepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the sameprocedure as reference example 12→reference example 28 (with the provisothat methyl 5-(chloroformyl)pentanoate was used instead of methyl4-(chloroformyl)-butyrate)→reference example 5→reference example 32, bythe same procedure as example 19.

TLC(ethyl acetate:methanol=10:1):Rf 0.50;

IR(cm⁻¹) ν 3034, 2941, 2872, 1729, 1674, 1617, 1578, 1510, 1466, 1411,1373, 1315, 1248, 1210, 1176, 1116, 1038, 1016, 998, 972, 845, 817.

Example 20 and 20(a) Example 20

3- 1-6(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-hydroxy-4-dimethylaminocarbonylbutyl)benzen-2-yl!propionicacid ##STR162##

Example 20(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-hydroxy-5-dimethylaminocarbonylpentyl)benzen-2-yl!propionicacid ##STR163##

The title compounds, of the present invention, having the followingphysical data were obtained with using the carboxylic acid prepared inreference example 19 and 19(a) by the same procedure as referenceexample 16.

Example 20:

TLC(ethyl acetate:methanol=9:1):Rf 0.48;

IR(cm⁻¹) ν 2936, 1723, 1609, 1511, 1468, 1403, 1249, 1176, 1120, 1035,

Example 20(a)

TLC(ethyl acetate:methanol=10:1):Rf 0.42;

IR(cm⁻¹): ν 2936, 2864, 1725, 1609, 1511, 1467, 1403, 1249, 1176, 1119,1035, 969, 814, 756.

Example 21

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-n-propoxybenzen-2-yl!propionic acid##STR164##

The title compound, of the present invention, having the followingphysical data was obtained with using 6-hydroxycoumarin prepared inreference example 25 by the same procedure as reference example 26 (withthe proviso that 1-bromo-n-propane was used instead of ethyl5-bromopentanoate)→reference example 27→reference example 2→referenceexample 4→reference example 5 and then purification by columnchromatography on silica gel.

TLC(ethyl acetate:n-hexane=1:1):Rf 0.30;

IR(cm¹): ν 2937, 1713, 1608, 1504, 1471, 1217, 1036.

Example 22

3-1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(4-dimethylaminocarbonyl-n-butyl)benzen-2-yl!propionicacid ##STR165##

The title compound, of the present invention, having the followingphysical data was obtained with using the ethyl ester prepared inreference example 31 by the same procedure as reference example10→reference example 23→reference example 14→reference example15→reference example 16→reference example 5 and then purification bycolumn chromatography on silica gel.

TLC(ethyl acetate):Rf 0.42;

IR(cm⁻¹) ν 3402, 2927, 2856, 1728, 1626, 1504, 1468, 1402, 1251, 1161,1121, 1058, 971, 908, 810, 723.

Example 23

3-1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-dimesylaminobenzen-2-yl!propionicacid ##STR166##

The title compound, of the present invention, having the followingphysical data was obtained with using the tert-butyl ester prepared inreference example 17 by the same procedure as reference example10→reference example 18→reference example 20→reference example11→reference example 12→reference example 13→reference example14→reference example 15→reference example 16→reference example 5 andthen purification by column chromatography on silica gel.

TLC(ethyl acetate):Rf 0.40;

IR(cm⁻¹) ν 3368, 2921, 2856, 1714, 1504, 1373, 1325, 1261, 1219, 1158,976, 921, 871, 762.

Example 24

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-carboxylbutyl)benzen-2-yl!propionicacid ##STR167##

The title compound, of the present invention, having the followingphysical data was obtained with using the dicarboxylic acid prepared inreference example 29 by the same procedure as reference example31→reference example 4→reference example 5 and then purification bycolumn chromatography on silica gel.

TLC(ethyl acetate:methanol=6:1):Rf 0.70;

IR(cm⁻¹): ν 3015, 2938, 2857, 1702, 1610, 1514, 1503, 1473, 1463, 1447,1422, 1408, 1341, 1305, 1288, 1250, 1202, 1179, 1118, 1040, 1020, 963,807

Example 24(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(5-carboxylpentyl)benzen-2-yl!propionicacid ##STR168##

The title compound, of the present invention, having the followingphysical data was obtained with using a dicarboxylic acid, which wasprepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the sameprocedure as reference example 12→reference example 28 (with the provisothat methyl 5-(chloroformyl)pentanoate was used instead of methyl4-(chloroformylbutyrate)→reference example 29, by the same procedure asexample 24.

TLC(ethyl acetate:methanol=20:1):Rf 0.68;

IR(cm⁻¹) ν 2932, 2853, 1709, 1609, 1512, 1500, 1465, 1420, 1289, 1245,1206, 1176, 1128, 1031, 966, 836, 814. 800.

Example 25

3- 1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(4-carboxyl-n-butyl)benzen-2-yl!propionicacid ##STR169##

The title compound, of the present invention, having the followingphysical data was obtained with using the carboxylic acid prepared inreference example 29 by the same procedure as reference example31→reference example 10→reference example 23→reference example14→reference example 15→reference example 16→reference example 5 andthen purification by column chromatography on silica gel.

TLC(ethyl acetate):Rf 0.33;

IR(cm⁻¹) ν 3426, 2922, 2855, 1719, 1703, 1611, 1503, 1465, 1447, 1429,1409, 1311, 1286, 1241, 1199, 1127, 1059, 1001, 975, 960, 806.

Example 26

3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-n-butylbenzen-2-yl!propionicacid ##STR170##

The title compound, of the present invention, having the followingphysical data was obtained with using 3-(1-methoxybenzen-2-yl)propionicacid by the same procedure as reference example 12→reference example 28(with the proviso that butyryl chloride was used instead of methyl4-(chloroformyl)butyrate)→reference example 16→reference example29→reference example 31→reference example 4→reference example 5 and thenpurification by column chromatography on silica gel.

TLC(n-hexane:ethyl acetate=2:1):Rf 0.48;

IR(cm⁻¹) ν 3003, 2931, 2858, 1708, 1609, 1577, 1510, 1467, 1456, 1442,1290, 1247, 1224, 1175, 1124, 1037, 967, 844, 804.

Example 27

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-oxo-4-carboxylbutyl)benzen-2-yl!propionicacid ##STR171##

The title compound, of the present invention, having the followingphysical data was obtained with using the dicarboxylic acid prepared inreference example 32 by the same procedure as reference example31→reference example 4→reference example 5 and then purification bycolumn chromatography on silica gel.

TLC(ethyl acetate:methanol=9:1):Rf 0.20;

IR(cm⁻¹): ν 2943, 1697, 1682, 1603, 1510, 1259, 1117

Example 27(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-oxo-5-carboxylpentyl)benzen-2-yl!propionicacid ##STR172##

The title compound of the present invention, having the followingphysical data was obtained with using a dicarboxylic acid, which wasprepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the sameprocedure as reference example 12→reference example 28 (with the provisothat methyl 4-(chloroformyl)pentanoate was used instead of methyl4-(chloroformyl)butyrate)→reference example 5→reference example 32, bythe same procedure as example 27.

TLC(ethyl acetate:methanol=20:1):Rf 0.45;

IR(cm⁻¹): ν 2939, 1709, 1694, 1682, 1604, 1578, 1511, 1300, 1260, 1245,1179, 1116, 1037, 973.

Example 28

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-hydroxy-4-carboxy(butyl)benzen-2-yl!propionicacid ##STR173##

The title compound, of the present invention, having the followingphysical data was obtained with using the dicarboxylic acid prepared inexample 27 by the same procedure as reference example 16.

TLC(ethyl acetate:methanol=9:1):Rf 0.20;

IR(cm⁻¹): ν 3401, 2938, 1608, 1558, 1511, 1409, 1249, 1176, 1119, 1034,968, 810.

Example 28(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(1-hydroxy-5-carboxylpentyl)benzen-2-yl!propionicacid ##STR174##

The title compound, of the present invention, having the followingphysical data was obtained with using the dicarboxylic acid prepared inexample 27(a) by the same procedure as example 28.

TLC(ethyl acetate:methanol=20:1):Rf 0.47;

IR(cm⁻¹) ν 3555, 3032, 2932, 2861, 1703, 1609, 1513, 1503, 1467, 1449,1427, 1408, 1286, 1250, 1211, 1178, 1122, 1036, 963, 808.

Example 29

3-1-(5E-7-hydroxypentadecenyl)oxy-3-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid ##STR175##

A residue was obtained with using 2,6-dimethoxybenzaldehyde by the sameprocedure as reference example 24→reference example 2→reference example25→reference example 26 (with the proviso thatN,N-dimethyl-5-bromopentanamide was used instead of ethyl5-bromopentanoate)→reference example 27 g reference example 10→reference example 23→reference example 14→reference example15→reference example 16→reference example 5. The residue was purified bycolumn chromatography on silica gel (chloroform:methanol=20:1) to givethe title compound having the following physical data.

TLC(chloroform:methanol=10:1):Rf 0.44;

IR(cm⁻¹): ν 2927, 2856, 1723, 1596, 1463, 1402, 1255, 1183, 1161, 1103,971, 776, 725

Example 30

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid ##STR176##

The title compound, of the present invention, having the followingphysical data was obtained with using 2,6-dimethoxybenzaldehyde by thesame procedure as reference example 24→reference example 2→referenceexample 25→reference example 26 (with the proviso thatN,N-dimethyl-5-bromopentanamide was used instead of ethyl5-bromopentanoate)→reference example 27→reference example 4→referenceexample 5 and then purification by column chromatography on silica gel.

TLC(chloroform:methanol=10:1):Rf 0.52;

IR(cm⁻¹): ν 2937, 1723, 1608, 1596, 1511, 1463, 1401, 1250, 1178, 1103,1035, 969, 846, 776, 756.

Example 30(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-(2-pyrrolidon-1-yl)-n-butoxy!benzen-2-yl!propionicacid ##STR177##

The title compound, of the present invention, having the followingphysical data was obtained with using 2,6-dimethoxybenzaldehyde by thesame procedure as example 30 (with the proviso that1-bromo-4-(2-pyrrolidon-1-yl)butane was used instead ofN,N-dimethyl-5-bromopentanamide)

TLC(chloroform:methanol=10:1):Rf 0.45;

IR(cm⁻¹): ν 2937, 1723, 1645, 1.595, 1511, 1463, 1389, 1250, 1178, 1103,1035, 969, 847, 756.

Example 30(b)

3- 1-6-(4-methoxyphenyl)hexyl!oxy-3-(4-dimethylamino-carbonylbutyl)oxybenzen-2-yl!propionicacid ##STR178##

The title compound, of the present invention, having the followingphysical data was obtained with using 2,6-dimethoxybenzaldehyde by thesame procedure as example 30 (with the proviso that6-(p-methoxyphenyl)hexanol methansulfonate was used instead of6-(p-methoxyphenyl)-5E-hexenol methansulfonate).

TLC(ethylacetate:methanol=9:1):Rf 0.30;

IR(cm⁻¹): ν 2933, 1724, 1596, 1513, 1463, 1248, 1103.

Examples 31

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(3-carboxylpropyl)oxybenzen-2-yl!propionicacid ##STR179##

The title compound, of the present invention, having the followingphysical data was obtained with using 2,6-dimethoxybenzaldehyde by thesame procedure as reference example 24→reference example 2→referenceexample 25→reference example 26 (with the proviso that ethyl4-bromobutyrate was used instead of ethyl 5-bromopentanoate)→referenceexample 27→reference example 4→reference example 5 and purification bycolumn chromatography on silica gel.

TLC(chloroform:methanol=10:1):Rf 0.35;

IR(cm⁻¹) ν 2937, 1707, 1559, 1511, 1463, 1250, 1177, 1104, 1036, 967,846. 775, 729.

Example 31(a)

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-carboxylbutyl)oxybenzen-2-yl!propionicacid ##STR180##

The title compound, of the present invention, having the followingphysical data was obtained with using 2,6-dimethoxybenzaldehyde by thesame procedure as example 31 (with the proviso that ethyl5-bromopentanoate was used instead of ethyl 4-bromobutyrate).

TLC(chloroform:methanol=10:1):Rf 0.37;

IR(cm⁻¹): ν 2937, 1699, 1595, 1510, 1460, 1250, 1180, 1160, 1034, 967,846, 773, 718

Example 31(b)

3- 1-6-(4-methoxyphenyl)hexyl!oxy-3-(4-carboxylbutyl)oxybenzen-2-yl!propionicacid ##STR181##

The title compound, of the present invention, having the followingphysical data was obtained with using the compound prepared in example31(a) by the same procedure as reference example 2 and then purificationby column chromatography on silica gel.

TLC(ethyl acetate:methanol=9:1):Rf 0.40;

IR(cm⁻¹): ν 2935, 1702, 1595, 1513, 1461, 1245, 1104.

Example 32

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-dimethyl-aminocarbonylbutanamido)benzen-2-yl!propionicacid ##STR182##

The title compound, of the present invention, having the followingphysical data was obtained with using 2-hydroxy-6-nitrobenzaldehyde,which was prepared with using 3-nitrophenol by the method described inBull. Chem. Soc. Japan, 46, 2903 (1973), by the same procedure asreference example 1→reference example 2→reference example 3→referenceexample 4→reference example 5→reference example 6 (with the proviso thatdimethylamine was used instead of morpholine)→example 1.

TLC(methylene chloride:methanol=4:1):Rf 0.52;

IR(cm⁻¹): ν 2936, 1608, 1511, 1456, 1248, 1176.

Example 33

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(5-carboxylpentyl)benzen-2-yl!propionicacid ##STR183##

The title compound, of the present invention, having the followingphysical data was obtained with using an ester, which was prepared withusing the ester prepared in reference example 36 by the same procedureas reference example 4, by the same procedure as reference example 5 andthen purification by column chromatography on silica gel.

TLC(chloroform:methanol=10:1);Rf 0.30;

MS: m/z 468(M⁺), 189;

IR(cm⁻¹): ν 2930, 1707, 1608, 1583, 1511, 1458, 1248, 1176, 1088, 1037,967, 846, 756.

Example 34

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(5-dimethylaminocarbonylpentyl)benzen-2-yl!propionicacid ##STR184##

The title compound, of the present invention, having the followingphysical data was obtained with using the ester prepared in referenceexample 36 by the same procedure as reference example 25→referenceexample 6 (with the proviso that dimethylamine was used instead ofmorpholine)→reference example 27→reference example 4→reference example 5and then purification by column chromatography on silica gel.

TLC(chloroform:methanol=10:1):Rf 0.48;

IR(cm⁻¹) ν 2932, 1724, 1609, 1510, 1458, 1402, 1249, 1176, 1087, 1037,969, 847, 791, 751.

Example 35

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-dimesylaminobenzen-2-yl!propionicacid ##STR185##

The title compound, of the present invention, having the followingphysical data was obtained with using 2-hydroxy-6-nitrobenzaldehyde bythe same procedure as reference example 1→reference example 2→referenceexample 17→reference example 4→reference example 18→reference example20→example 1.

NMR: δ 1.67 (2H, m), 1.88 (2H, m), 2.27 (2H, m), 2.73 (2H, m), 3.09 (2H,m), 3.47 (6H, s), 3.80 (3H, s), 4.03 (2H, t), 6.08 (1H, dt), 6.35 (1H,d), 6.79-7.02 (4H, m), 7.18-7.33 (3H, m).

Example 36

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(perhydro-1,2-thiazin-1,1,3-trione-2-yl)benzen-2-yl!propionicacid ##STR186##

The title compound, of the present invention, having the followingphysical data was obtained with using 2-hydroxy-6-nitrobenzaldehyde bythe same procedure as reference example 1→reference example 2→referenceexample 17→reference example 4→reference example 18→reference example3→reference example 5→reference example 22→example 1.

NMR: δ 1.66 (2H, m), 1.86 (2H, m), 2.27 (2H, m), 2.44 (2H, m), 2.63 (2H,m), 2.77-3.00 (4H, m), 3.59 (2H, t, J=6 Hz), 3.79 (3H, s), 4.02 (2H, m),6.08 (1H, dt, J=16 Hz, 7 Hz), 6.35 (1H, d, J=16 Hz), 6.78-6.99 (4H, m),7.18-7.34 (3H, m).

Example 37

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(1-oxo-5-carboxylpentyl)benzen-2-yl!propionicacid ##STR187##

A residue was obtained with using the carboxylic acid prepared inreference example 40 by the same procedure as reference examples25→reference example 27→reference example 31→reference example4→reference example 5. The residue was purified by column chromatographyon silica gel (chloroform:methanol=20:1→10:1) to give the titlecompound, of the present invention, having the following physical data.

TLC(chloroform:methanol=10:1):Rf 0.32;

IR(cm⁻¹): ν 2934, 1706, 1608, 1579, 1511, 1454, 1248, 1176, 1036, 968,846, 757.

Example 38

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(1-hydroxy-5-carboxylpentyl)benzen-2-yl!propionicacid ##STR188##

The title compound, of the present invention, having the followingphysical data was obtained with using the carboxylic acid prepared inexample 37 by the same procedure as reference example 16.

TLC(chloroform:methanol=10:1):Rf 0.24;

IR(cm⁻¹): ν 2937, 1708, 1608, 1585, 1511, 1459, 1250, 1176, 1036, 968,846, 794, 756.

Example 39

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(1-oxo-5-dimethylaminocarbonylpentyl)benzen-2-yl!propionicacid ##STR189##

The title compound, of the present invention, having the followingphysical data was obtained with using the carboxylic acid prepared inreference example 40 by the same procedure as reference example25→reference example 27→reference example 6 (with the proviso thatdimethylamine was used instead of morpholine)→reference example4→reference example 5 and then purification by column chromatography onsilica gel.

TLC(chloroform:methanol=10:1):Rf 0.48;

IR(cm⁻¹): ν 2942, 1723, 1674, 1626, 1577, 1512, 1453, 1418, 1398, 1250,1181, 1018, 987, 964, 907, 842, 812, 785, 744.

Example 40

3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(1-hydroxy-5-dimethylaminocarbonylpentyl)benzen-2-yl!propionicacid ##STR190##

The title compound, of the present invention, having the followingphysical data was obtained with using the carboxylic acid prepared inexample 39 by the same procedure as reference example 16.

TLC(chloroform:methanol=10:1):Rf 0.35;

IR(cm⁻¹): ν 2937, 1718, 1608, 1511, 1460, 1403, 1249, 1176, 1067, 1036,969, 847, 795, 755.

Formation Example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

    ______________________________________                                        3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-                                                         5.0 g                                                carboxylbutyl)oxybenzen-2-yl!propionic acid                                   Cetlulose calcium glycolate                                                                            0.2 g                                                (carboxymethylcellulose calcium)                                              (disintegrating agent)                                                        Magnesium stearate       0.1 g                                                (Lubricating agent)                                                           Microcrystaline cellulose                                                                              4.7 g                                                ______________________________________                                    

    ______________________________________                                        Ex. No. Name                                                                  ______________________________________                                        1(a)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-                                dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(b)    3- 1-n-hexyloxy-4-(4-dimethylaminocarbonyl-                                   butanamido)benzen-2-yl!proponic acid                                  1(c)    3- 1-n-dodecyloxy-4-(4-dimethylaminocarbonyl-                                 butanamido)benzen-2-yl!propionic acid                                 1(d)    3- 1-n-hexadecyloxy-4-(4-dimethylaminocarbonyl-                               butanamido)benzen-2-yl!propionic acid                                 1(e)    3- 1- 6-(4-n-propoxyphenyl)hex-5E-enyl!oxy-4-(4-                              dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(f)    3- 1- 6- 4-(2-propenyl)oxyphenyl!hex-5E-enyl!oxy-4-                           (4-dimethylaminocarbonylbutanamido)benzen-2-                                  yl!propionic acid                                                     1(g)    3- 1- 7-(4-methoxyphenyl)hept-6E-enyl!oxy-4-                                  (4-dimethylaminocarbonylbutanamido)benzen-2-                                  yl!propionic acid                                                     1(h)    3- 1- 7-(4-methoxyphenyl)-n-heptyl!oxy-4-                                     (4-dimethylaminocarbonylbutanamido)benzen-2-                                  yl!propionic acid                                                     1(i)    3- 1- 6-(4-n-pentyloxyphenyl)hex-5E-enyl!oxy-4-                               (4-dimethylaminocarbonylbutanamido)benzen-2-                                  yl!propionic acid                                                     1(j)    3- 1- 6-(4-methoxyphenyl)-n-hexyl!oxy-4-                                      (4-dimethylaminocarbonylbutanamido)benzen-2-                                  yl!propionic acid                                                     1(k)    3- 1-(7-phenylhept-6E-enyl)oxy-4-(4-dimethylamino-                            carbonylbutanamido)benzen-2-yl!propionic acid                         1(l)    3- 1- 6-(2-methoxyphenyl)hex-5E-enyl!oxy-4-(4-                                dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(m)    3- 1- 6-(3-methoxyphenyl)hex-5E-enyl!oxy-4-(4-                                dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(n)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4- 4-(1-                             indolinyl)carbonylbutanamido!-benzen-2-yl!propionic                           acid                                                                  1(o)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4- 4-(2-                             thiazo-yl)aminocarbonylbutanamido!benzen-2-                                   yl!propionic acid                                                     1(p)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-                                dimethylaminocarbonylpropionamido)benzen-2-                                   yl!propionic acid                                                     1(q)    3- 1- 6-(4-methylthiophenyl)hex-5E-enyl!oxy-4-(4-                             dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(r)    3- 1- 6-(3,4-dimethoxyphenyl)hex-5E-enyl!oxy-4-(4-                            dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(s)    3- 1- 6-(4-methylphenyl)hex-5E-enyl!oxy-4-(4-                                 dimethylaminocarbonylbutanamido)benzen-2                                      yl!propionic acid                                                     1(t)    3- 1- 6-(4-chtorophenyl)hex-5E-enyl!oxy-4-(4-                                 dimethylaminocarbonylbutanamido)benzen-2-                                     yl!propionic acid                                                     1(u)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-                                dimethylaminocarbonylbenzamido)benzen-2-yl!propionic                          acid                                                                  2(a)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-                                carboxylbutanamido)benzen-2-yl!-E-acrylic acid                        2(b)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-                                carboxylbenzamido)benzen-2-yl!propionic acid                          3(a)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-                                   benzamidobenzen-2-yl!propionic acid                                   3(b)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-                                   decanamidobenzen-2-yl!propionic acid                                  3(c)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-                                   acetamidobenzen-2-yl!propionic acid                                   4(a)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-                                hydroxybutanamido)benzen-2-yl!propionic acid                          4(b)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-                                hydroxymethylbenzamido)benzen-2yl!propionic acid                      5(a)    3- 1-(4E-6-hydroxyletradecenyl)oxy-4-dimethylamino-                           carbonylbutanamidobenzen-2-yl!propionic acid                          5(b)    3- 1-(5E-7-hydroxydodecenyl)oxy-4-dimethylamino-                              carbonylbutanamidobenzen-2-yl!propionic acid                          5(c)    3- 1-(5E-7-hydroxy-9-(4-methoxyphenyl)nonenyl!oxy-                            4-dimethylaminocarbonylbutanamidobenzen-2-                                    yl!propionic acid                                                     5(d)    3- 1-(5E-7-hydroxynonenyl)oxy-4-dimethylamino-                                carbonylbutanamidobenzen-2-yl!propionic acid                          5(e)    3- 1-(5E-7-hydroxy-7-cyclohexylheptenyl)oxy-4-                                dimethylaminocarbonylbutanamidobenzen-2-yl!propionic                          acid                                                                  6(a)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-                                methylphenyl)sulfonylaminobenzen-2-yl!propionic acid                  6(b)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-methyl-                            sulfonylaminobenzen-2-yl!propionic acid                               6(c)    3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-benzyl-                            sulfonylaminobenzen-2-yl!propionic acid                               10(a)   3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-                                   ditosylaminobenzen-2-yl!propionic acid                                10(b)   3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-bis(n-                             butylsulfonyl)aminobenzen-2-yl!propionic acid                         10(c)   3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-                                   bis(benzylsulfonyl)aminobenzen-2-yl!propionic acid                    12(a)   3- 1- 6-(4-methoxyphenyl)hexyl!oxy-4-                                         (perhydro-1,2-thiazin-1,1,3-trione-2-yl)benzen-2-                             yl!propionic acid                                                     12(b)   3- 1- 6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-                                   (isothiazolidin-1,1,3-trione-2-yl)benzen-2-yl!propionic                       acid                                                                  15(a)   3- 1- 5E-7-hydroxy-9-(4-methoxyphenyl)nonenyl!oxy-                            4-(4-carboxylbutyl)oxybenzen-2-yl!propionic acid                      15(b)   3- 1-(5E-7-hydroxypentadecenyl)oxy-4-(3-                                      carboxylpropyl)oxybenzen-2-yl!propionic acid                          15(c)   3- 1-(5E-7-hydroxypentadecenyl)oxy-4-                                         carboxylmethoxybenzen-2-yl!propionic acid                             ______________________________________                                    

What is claimed is:
 1. A phenylkan(en)oic acid of the formula:##STR191## wherein A is: --O--;W is:i) C₁₋₁₃ alkylene, ii) phenylene, or##STR192## R¹ is: i) hydrogen, ii) C₁₋₄ alkyl, iii) --COOH, iv)##STR193## or v) --CH₂ OH; two R² are the same or different,i) hydrogenor ii) C₁₋₄ alkyl; Y is ethylene or vinylene; D is:i) --Z--B, or##STR194## Z is C₃₋₁₁ alkylene or alkenylene; B is ##STR195## R³ is: i)hydrogen, ii) halogen, iii) C₁₋₈ alkyl, alkoxy or alkylthio, or iv) C₂₋₈alkenyl, alkenyloxy or alkenylthio; n is 1-3; R⁴ is C₁₋₇ alkylene; R⁵is:i) C₁₋₁₂ alkyl, ii) C₂₋₁₂ alkenyl, iii) C₅₋₇ cycloalkyl, or iv)phenethyl or phenethyl wherein the ring is substituted by one C₁₋₄alkoxy; with the proviso that:i) --A--W--R¹ should bind to the 3- or4-carbon in the benzene ring, and ii) when W is phenylene or ##STR196##A does not represent --O--; and non-toxic salts thereof.
 2. A compoundaccording to claim 1, which is3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-carboxylbutoxy)benzen-2-yl!propionicacid, 3-1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(4-carboxylbutyl)oxybenzen-2-yl!propionicacid, 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid, 3-1-(5E-7-hydroxy-n-pentadecenyl)oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid, 3-1-(5E-7-hydroxypentadecenyl)oxy-3-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid, 3- 1-5E,9Z-7-hydroxy-n-pentadecenyl!oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid, 3- 1-5E-7-hydroxy-9-(4-methoxyphenyl)nonenyl!oxy-4-(4-carboxylbutyl)oxybenzen-2-yl!propionicacid, 3-1-(5E-7-hydroxypentadecenyl)oxy-4-(3-carboxylpropyl)-oxybenzen-2-yl!propionicacid, 3-1-(5E-7-hydroxypentadecenyl)oxy-4-carboxylmethoxybenzen-2-yl!propionicacid, 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-n-propoxybenzen-2-yl!propionicacid, 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid, 3-1-(5E-6-methyl-7-hydroxy-n-pentadecenyl)oxy-4-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionicacid, 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-4-(3-dimethylaminocarbonyl-n-propyl)oxybenzen-2-yl!propionicacid, 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(3-carboxylpropyl)oxybenzen-2-yl!propionicacid, 3- 1-6-(4-methoxyphenyl)hex-5E-enyl!oxy-3-(4-carboxylbutyl)oxybenzen-2-yl!propionicacid, 3- 1- 6-(4-methoxyphenyl)hexyl!oxy-3-(4-dimethylaminocarbonylbutyl)oxybenzen-2-yl!propionic acid or 3- 1-6-(4-methoxyphenyl)hexyl!oxy-3-(4-carboxylbutyl)-oxybenzen-2-yl!propionicacid.
 3. A method for the treatment of diseases induced by leukotrieneB₄, which comprises the administration of an effective amount of thephenylalkan(en)oic acid of the formula (I) as claimed in claim 1, or thepharmaceutically acceptable acid addition salts thereof.